CN105793254B - 氮杂喹唑啉羧酰胺衍生物 - Google Patents
氮杂喹唑啉羧酰胺衍生物 Download PDFInfo
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- CN105793254B CN105793254B CN201380071357.2A CN201380071357A CN105793254B CN 105793254 B CN105793254 B CN 105793254B CN 201380071357 A CN201380071357 A CN 201380071357A CN 105793254 B CN105793254 B CN 105793254B
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- phenyl
- pyrimidine
- ethylamino
- pyrido
- carboxylic acid
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Abstract
Description
相关申请
本申请要求2012年11月29日提交的美国临时专利申请号61/731,075的优先权,其内容全部纳入此处作为参考。
技术领域
本发明涉及通式(I)所示的化合物和/或其生理学上可接受的盐,
式中,W1、W2、W3、W4、R1、R2、R3和m具有下文中所给的意义。通式(I)所示的化合物可用作p70S6K抑制剂。本发明的其它方面包括包含通式(I)所示的化合物的药物组合物,以及通式(I)所示的化合物在治疗过度增殖性疾病的用途。
发明背景
蛋白激酶组成一大族担负细胞内多种信号转导过程控制的结构相关酶(Hardie,G.和Hanks,S.(1995)The Protein Kinase Facts Book.I和II,Academic Press,SanDiego,CA)。通过它们磷酸化的底物(例如蛋白-酪氨酸、蛋白-丝氨酸/苏氨酸、脂质等),可将激酶分成多族。已确定了一般对应于这些激酶各族的序列模体(例如,Hanks&Hunter,FASEB J.,9:576-596(1995);Knighton,等人,Science,253:407-414(1991);Hiles等人,Cell,70:419-429(1992);Kunz等人,Cell,73:585-596(1993);Garcia-Bustos,等人,EMBOJ.,13:2352-2361(1994))。
蛋白激酶可由其调节机制表征。这些机制包括例如自磷酸化作用、由其它激酶转磷酸作用、蛋白质-蛋白质相互作用、蛋白质-脂质相互作用和蛋白质-多核苷酸相互作用。单个蛋白激酶可由多于一种机制调节。
通过将磷酸基团加到靶蛋白,激酶可调节很多不同的细胞过程,包括但不限于增殖、分化、细胞凋亡、运动性、转录、翻译及其他信号传导过程。这些磷酸化事件充当能够调节或调整靶蛋白生物功能的分子通断开关。靶蛋白的磷酸化响应于多种胞外信号(激素、神经递质、生长和分化因子等)、细胞周期事件、环境或营养应激等而发生。适合的蛋白激酶参与信号传导通路,以活化或钝化(直接或间接)例如代谢酶、调节蛋白、受体、细胞骨架蛋白、离子通道或泵或转录因子。由蛋白磷酸化控制缺陷导致的不受控的信号传导涉及多种疾病,包括例如炎症、癌症、过敏/哮喘、免疫系统疾病和病症、中枢神经系统疾病和病症及血管生成。
蛋白激酶70S6K,即70kDa核糖体蛋白激酶p70S6K(也称为SK6、p70/p85S6激酶、p70/p85核糖体S6激酶和pp70S6K)是蛋白激酶的AGC亚家族的成员。p70S6K是丝氨酸-苏氨酸激酶,其是磷脂酰肌醇3激酶(PI3K)/AKT通路的组成部分。p70S6K为PI3K的下游部分,且通过响应多种有丝分裂原、激素和生长因子在多个位点的磷酸化而被激活。由于雷帕霉素起到抑制p70S6K活性的作用,p70S6K活性也受包含mTOR的复合物(TORC1)的控制。p70S6K通过PI3K下游靶点AKT和PKCζ调节。Akt直接磷酸化并钝化TSC2,由此激活mTOR。此外,对于被渥曼青霉素抑制而不被雷帕霉素抑制的p70S6K的突变体等位基因的研究表明PI3K通路可以不依赖mTOR活性的调节而对p70S6K产生作用。
酶p70S6K通过S6核糖体蛋白的磷酸化而调控蛋白合成。S6磷酸化与翻译装置(translational apparatus)的mRNA编码组件的翻译的增加相关,所述翻译装置包括核糖体蛋白和翻译延伸因子(其表达增加对细胞生长和增殖是必不可少的)。这些mRNA在其5′转录起始端(称为5′TOP)包含寡嘧啶片段,已证明这对于其在翻译水平的调节是必不可少的。
除了参与翻译之外,p70S6K激活还涉及细胞周期控制、神经细胞分化、在肿瘤转移中重要的细胞运动性和细胞响应的调节、免疫应答和组织修复。p70S6K抗体破坏了大鼠成纤维细胞进入S期所驱动的促有丝分裂响应,这就表明了p70S6K功能在细胞周期中从G1期至S期的进程中是必不可少的。此外,已经确定在细胞周期的G1期至S期雷帕霉素对细胞周期增殖的抑制是其抑制生成过度磷酸化的激活形式的p70S6K的结果。
p70S6K肿瘤细胞增殖和保护细胞免于细胞凋亡中的作用受到支持,这是基于其在肿瘤组织中参与生长因子受体信号转导、过表达和激活。例如,RNA印迹分析和蛋白质印迹分析表明,PS6K基因的扩增分别伴有mRNA和蛋白质表达的相应增加(Cancer Res.(1999)59:1408-11-PS6K在乳腺癌中定位于染色体区17q23及其扩增的测定(Localization ofPS6K to Chromosomal Region 17q23 and Determination of Its Amplification inBreast Cancer))。
染色体17q23在以下肿瘤和癌症中扩增:高达20%的原发性乳腺肿瘤、87%含有BRCA2突变的乳腺肿瘤和50%含有BRCA1突变的肿瘤以及其它癌症类型,例如胰腺癌、膀胱癌和成神经细胞瘤(参见Barlund等人,Cancer Res.,60:5340-5346(2000))。研究表明,17q23在乳腺癌中的扩增涉及PAT1、RAD51C、PS6K和SIGMA1B基因(Cancer Res.(2000):60,第5371-5375页)。p70S6K基因已被鉴定为这些部位扩增和过表达的靶点,并且观察到扩增和预后不良之间在统计上显著相关。
在用上游激酶mTOR的抑制剂CCI-779(雷帕霉素酯)治疗的肾癌患者中,观察到p70S6K激活的临床抑制。据报道,疾病进程和p70S6K活性抑制之间有显著的线性相关性。在响应能量应激时肿瘤抑制因子LKB1激活AMPK,AMPK磷酸化TSC1/2复合物,并使得其钝化mTOR/p70S6K通路。LKB1中的突变引起波伊茨-耶格综合征(Peutz-Jeghers syndromePJS),患有PJS的患者发展为的癌症可能性是一般人群的15倍。此外,1/3的肺腺癌潜伏有未激活的LKB1突变。
p70S6K涉及代谢疾病和障碍。据报道,缺乏p70S6K避免患年龄和饮食诱发的肥胖症并同时提高胰岛素敏感性。基于这些发现,支持了p70S6K在肥胖症、糖尿病、代谢综合征、胰岛素抵抗、高血糖、高氨基酸血症和高脂血症等代谢疾病和障碍中的作用。
在WO03/064397、WO04/092154、WO05/054237、WO05/056014、WO05/033086、WO05/117909、WO05/039506、WO06/120573、WO06/136821、WO06/071819、WO06/131835、WO08/140947、WO10/093419、以及WO12/069146中公开了被描述为适于抑制p70S6K的化合物。
在某种程度上,aurora激酶通过细胞周期和有丝分裂调节细胞的进程。癌细胞的生理特点是通过细胞周期和有丝分裂使正常进程发生病理变化。据记载,抑制aurora激酶的某些化合物还与受损的染色体排列、有丝分裂关卡和多倍体的弱化、以及随后的细胞死亡有关。更具体地,抑制aurora B激酶已被证明在若干临床试验中由于剂量限制性毒性而引起白细胞减少(Dar等人,Mol Cancer Ther 9:268-278(2010))。此外,抑制aurora B激酶在竞争性ATP激酶抑制剂中引起脱靶效应。预计这些aurora B激酶抑制剂也将显示,抑制aurora B激酶会因为剂量限制性毒性而引起白细胞减少,因此具有有限的治疗窗。此外,一些aurora激酶抑制剂还可以在正常乳腺上皮细胞培养物中诱导多倍体,从而产生不利的长期临床问题。
因此,可以预期的是,p70S6K抑制剂基本上消除或显著降低aurora B激酶的抑制,通过降低由于剂量限制性毒性而引起白细胞减少症而在治疗过度增殖性疾病(如癌症)中保持特殊的前景,籍此提高了这些化合物的治疗窗口。此外,可以预期的是,p70S6K抑制剂也抑制激酶的Akt(位于PI3K通路中p70S6K的上游),有效地切断PI3K通路(Choo等人,PNASUSA105(45):17414-9(2008)),并允许捕获任何Akt反馈回路的激活(Tamburini等人,Blood111:379-82(2008))。
发明内容
本发明的目的是发现具有有价值的特性的新型化合物,尤其是可用于制备药物的化合物。业已惊奇地发现,本发明的化合物及其盐具有高的药学价值特性,又有良好的耐药性。具体地,它们作为p70S6K抑制剂,任选地作为Akt抑制剂。
本发明的一方面提供通式(I)所示的化合物,
式中,
W1、W2、W3、W4 各自独立地是N或者CH,其中W1、W2、W3或者W4中至少之一是N;
R1 是Ar或者Het1;
R2、R4、R5 各自独立地是Y;
R3 是Y或者-(CH2)p-NR4R5;
R2和R3 与各自所连接的原子一起可以形成-(CH2)n-NY-(CH2)p;
R4和R5 与各自所连接的原子一起可以形成-(CY2)q-;
Y 是H或者A;
A 是具有1-10个碳原子的无支链的或有支链的烷基,其中1-7个H原子可以相互独立地被Hal所替代,
Ar 是含有3-10个碳原子的不饱和或者芳香族单环或者双环的碳环,所述碳环可被至少一个选自以下组内的取代基取代:Hal、A、OY、CN、COY、COOY、CONYY、NYCOY、NYCONYY、SO2Y、SO2NYY、NYSO2Y、NYY、NO2、OCN、SCN、SH,所述取代基任选地被苯基和Het1取代;
Het1 是含有2-10个碳原子和1-4个N、O和/或S原子的不饱和或者芳香族单环或者双环的杂环,所述杂环可被至少一个选自以下组内的取代基取代:Hal、A、OY、CN、COY、COOY、CONYY、NYCOY、NYCONYY、SO2Y、SO2NYY、NYSO2Y、NYY、NO2、OCN、SCN、SH,所述取代基任选地被苯基和Het2取代;
Het2 是含有2-5个碳原子和1-3个N、O和/或S原子的任选地取代的饱和、不饱和或者芳香族单环的5-6元杂环;
Hal 是F、Cl、Br或者I;
m 是0或者1;
n或者p 各自独立地是0、1、2或者3;以及
q 是2、3、4、5或者6;
和/或其生理学上可接受的盐。
具体实施方式
在本发明的意义内,化合物被定义为包括其药学上可用的衍生物、溶剂化物、前药、互变异构体、对映体、外消旋体和立体异构体,包括以任何比例混合的混合物。
术语“药学上可用的衍生物”用来表示,例如,本发明化合物的盐类和所谓的药物前体化合物。术语“化合物的溶剂化物”用来表示这些化合物与惰性溶剂分子由于彼此引力作用而形成的加合物。溶剂化物是,例如,单水合物或双水合物或醇化物。当然,本发明还涉及本发明化合物的盐的溶剂化物。术语“前药”用来表示用例如烷基或酰基、糖或寡肽修饰的本发明化合物,它们在机体内迅速裂解形成活性形式的本发明化合物。这些也包括可生物降解的本发明化合物的聚合衍生物,例如见Int.J.Pharm.115,61-67(1995)中所述。同样地,可以将本发明化合物做成任何所希望的前药形式,例如酯类、碳酸盐、氨基甲酸盐、脲、酰胺或磷酸盐,在这些情况下实际具有生物活性的形式只能通过代谢被释放出来。任何在体内可被转化为生物活性剂(例如本发明的化合物)的任何化合物都是本发明范围和意义内的前药。各种形式的前药已为本领域所公知和记载(例如Wermuth CG等人,Chapter 31:671-696,The Practice of Medicinal Chemistry,Academic Press 1996;Bundgaard H,Design of ProdrugS,Elsevier 1985;Bundgaard H,Chapter 5:131-191,A Textbook ofDrug Design and Development,Harwood Academic Publishers 1991)。此处纳入所述全部文献作为参考。进一步已知的是,化学物质在体内被转化为代谢物,后者在适合的条件下同样可诱发所希望的生物作用-在某些情况下,甚至以更显著的方式发挥所希望的生物作用。本发明任一化合物在体内通过代谢转化为任何具有生物活性的化合物都是本发明范围和意义内的代谢产物。
本发明的化合物可以是其双键异构体形式(如纯的E或Z异构体),或者是这些双键异构体的混合物形式。如果可能的话,本发明的化合物可以是互变异构体形式,如酮-烯醇互变异构体。本发明考虑本发明化合物全部立体异构体,可以是混合物形式、纯的形式或者大致纯的形式。本发明化合物中的任一碳原子可以具有不对称中心。因此,它们可以其外消旋体形式、纯的对映体和/或非对映体形式、或者这些对映体和/或非对映体的混合物形式存在。混合物可以具有所希望的立体异构体的混合比例。这样,例如通过本身已知的方法可以将具有一个或多个手性中心以及以外消旋体或非对映体混合物形式存在的本发明化合物拆分为它们的光学纯异构体,即对映体或非对映体。本发明化合物的拆分可以利用针对手性或非手性相的柱拆分法、或者在任选的光学活性溶剂中重结晶、或者利用光学活性酸或碱、或者利用光学活性剂(如光学活性醇)进行衍生化再除去基团来实现。
本发明也涉及本发明的化合物的混合物的用途,例如两种非对映体的混合物,例如混合比例为1:1,1:2,1:3,1:4,1:5,1:10,1:100或1:1000。这些混合物特别优选立体异构体化合物的混合物。
本说明书所用的定义化合物,尤其是本发明的化合物,的术语通常基于IUPAC组织关于化合物特别是有机化合物的规则。解释本发明的上述化合物的术语总是具有如下含义,除非在说明书或权利要求中另有所指。
术语“未取代的”指的是相应的原子团、基团或部分没有取代基。术语"取代的"指的是相应的原子团、基团或部分具有一或多个取代。若某个原子团有多个取代基并指定选定的多个取代基,则选定的取代基相互独立,并且不一定相同。即使某个原子团有多个指定的取代基(例如Y2或YY),该取代基的表示可以相互不同(例如甲基和乙基)。因此,可以理解的是,本发明任一个原子团的某些取代可以涉及相同或不同的原子团。所以,如果各个原子团在一个化合物内出现多次,这些原子团适用上述的含义,各自相互地独立。如果有多个取代,原子团可以交替地用R’、R”、R”’、R””等等来表示。
术语“烷基”或“A”表示非环状的饱和或不饱和烃基,它们是直链或支链的,较佳为具有1、2、3、4、5、6、7、8、9或10个碳原子,即C1-10-烷基。烷基的例子有甲基、乙基、丙基、异丙基、1,1-,1,2-或2,2-二甲基丙基、1-乙基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基、丁基、异丁基、仲丁基、叔丁基、1-,2-或3-甲基丁基、1,1-,1,2-,1,3-,2,2-,2,3-或3,3-二甲基丁基、1-或2-乙基丁基、戊基、异戊基、新戊基、叔戊基、1-,2-,3-或4-甲基戊基、己基、2-己基、异己基,庚基、辛基、壬基、癸基、十一烷基、十二烷基、十四烷基、十六烷基、十八烷基、二十烷基、二十二烷基。
在本发明的一个优选实施方案中,A是具有1-10个碳原子的直链或支链烷基,其中1-7个氢原子可相互独立地被Hal取代。A更优选表示具有1-6个碳原子的直链或支链烷基,其中1-4个氢原子可相互独立地被Hal取代。在本发明的一最优选实施例中,A是具有1-4个碳原子的直链或支链烷基,其中1-3个氢原子可相互独立地被Hal取代。高度优选的是,A是具有1-4个碳原子的直链或支链烷基,其中1-3个氢原子可相互独立地被F和/或Cl取代。特别的选择是C1-4-烷基。C1-4-烷基是例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1,1-三氟乙基或溴甲基,特别是甲基、乙基、丙基或三氟甲基。不言而喻,本发明的任何基团中A的各自含义是各自独立的。
术语“碳环”或“碳环基”在本发明的意义上表示单环或多环的羟系统,包含3-14个,较佳为4-10个,特佳为6-8个环原子。环系统可以是饱和的单环,或者多环不饱和,或者芳香族。
术语“芳基”或“碳芳基”在本发明的意义上表示具有3-14个碳原子(较佳为4-10个碳原子,特佳为6-8个碳原子)的单环或多环芳烃系统,所述芳烃系统可被任意地取代。术语“芳基”也包括芳环是二环或多环饱和、部分不饱和和/或芳香族系统的一部分,例如,当芳环经芳基的任何合乎要求和可能的环原子稠合到本说明书定义的芳基、环烷基、杂芳基或杂环基上时。经芳基的任何环原子可进行与通式(I)化合物的连接。合适的芳基的例子是苯基、联苯基、萘基、1-萘基、2-萘基和蒽基,同样可以是二氢茚基、茚基、1,2,3,4-四氢萘基。优选的本发明的碳芳基是可被任意取代的苯基、萘基和联苯基,更优选的是可被任意取代的具有6-8个碳原子的单环碳芳基,最优选的是可被任意取代的苯基。
在本发明的一实施例中,碳环包括但不限于碳芳基,定义为“Ar”。合适的Ar基团的例子是苯基、o-,m-或p-甲苯基、o-,m-或p-乙基苯基、o-,m-或p-丙基苯基、o-,m-或p-异丙基苯基、o-,m-或p-叔丁基苯基、o-,m-或p-羟基苯基、o-,m-或p-甲氧基苯基、o-,m-或p-乙氧基苯基、o-,m-或p-氟苯基、o-,m-或p-溴苯基、o-,m-或p-氯苯基、o-,m-或p-磺酰基氨基苯基、o-,m-或p-(N-甲基-磺酰基氨基)苯基、o-,m-或p-(N,N-二甲基-磺酰基氨基)苯基、o-,m-或p-(N-乙基-N-甲基-磺酰基氨基)苯基、o-,m-或p-(N,N-二乙基-磺酰基氨基)苯基,特别是2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氟苯基、2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氯苯基、2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二溴苯基、2,3,4-,2,3,5-,2,3,6-,2,4,6-或3,4,5-三氯苯基、2,4,6-三甲氧基苯基、2-羟基-3,5-二氯苯基、p-碘苯基、4-氟-3-氯苯基、4-氯-3-氟苯基、4-氟-3-三氟甲基苯基、4-氯-3-氟苯基、4-氯-3-三氟甲基苯基、4-氯-3-甲氧基苯基、3-氰基-4-氯-苯基、2-氟-4-溴苯基、2,5-二氯-4-溴苯基、3-溴-6-甲氧基苯基、3-氯-6-甲氧基苯基或2,5-二甲基-4-氯苯基。
Ar优选表示含有3-10个碳原子的不饱和或芳香族单环或双环的碳环,该碳环可被至少一个选自Hal、A、OY、CN、COY、COOY、CONYY、NYCOY、NYCONYY、SO2Y、SO2NYY、NYSO2Y、NYY、NO2、OCN、SCN、SH的取代基取代,其中所述取代基任选地被苯基和Het1取代。在本发明的一优选实施例中,Ar表示含有4-8个碳原子的单环芳基,该芳基可被至少一个选自Hal、A、OY或CN的取代基取代。更优的是,Ar表示苯基,该苯基可被至少一个选自Hal、A、OA或CN的取代基取代。在本发明特别高度优选的实施例中,Ar表示苯基,所述苯基可被Hal和A二取代。
术语“杂环”或“杂环基”在本发明意义上表示具有包括碳原子和1、2、3、4或5个相同或不同杂原子(特别是氮、氧和/或硫)的3-14个环原子(较佳为4-10个环原子,特佳为4-8个环原子)的单环或多环系统。环系统可以是饱和的或一元或多元不饱和或者芳香族。对于环系统由至少两个环组成的情形,所述环可以通过稠合或螺合而连接在一起。这些杂环基可通过任何环原子连接。术语“杂环基”包括一些系统,其中杂环是二环或多环饱和、部分不饱和和/或芳香族系统的一部分,例如,当杂环经任何合乎要求的和可能的杂环基上的原子稠合到本说明书定义的芳基、环烷基、杂芳基或杂环基上时。经杂环基的任何环原子可进行与通式(I)化合物的连接。合适的杂环基的例子为:吡咯烷基、硫代吡咯烷基、哌啶基、吡嗪基、噁吡嗪基、噁哌啶基、噁二唑基、四氢呋喃基、咪唑烷基、噻唑烷基、四氢吡喃基、吗啉基、四氢硫代苯基、二氢吡喃基。
术语“杂芳基”在本发明的意义上表示1-15元、优选1-9元、特别优选5-,6-或7-元单环或多环芳烃基,包含至少一个(如果合适,还可为2、3、4或5个)杂原子,特别是氮、氧和/或硫,杂原子可以是相同或不同的。氮原子的数目较佳为0、1、2、3或4,氧原子和硫原子的数目相互独立地为0或1。术语“杂芳基”包括一些系统,其中芳环是二环或多环饱和、部分不饱和和/或芳香族系统的一部分,例如,当芳环经杂芳基的任何合乎要求的和可能的环原子稠合到本说明书定义的芳基、环烷基、杂芳基或杂环基上时。经杂芳基的任何环原子可进行与通式(I)化合物的连接。合适的杂芳基的例子是吡咯基、噻吩基、呋喃基、咪唑基、噻唑基,异噻唑基、噁唑基、噁二唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、喹啉基、异喹啉基、咪唑基、三唑基、三嗪基、四唑基、酞嗪基、吲唑基、吲嗪基、喹喔啉基、喹唑啉基、喋啶基、咔唑基、吩嗪基、吩噁嗪基、吩噻嗪基和吖啶基。
杂芳基在“Het1”的意义上较佳为表示具有2-10个碳原子和1-4个N、O和/或S原子的不饱和或芳香族单环或双环杂环,它可被至少一个选自Hal、A、OY、CN、COY、COOY、CONYY、NYCOY、NYCONYY、SO2Y、SO2NYY、NYSO2Y、NYY、NO2、OCN、SCN、SH的取代基取代,其中所述取代基任选地被苯基和Het2取代。在更优选的本发明实施例中,Het1表示具有4-8个碳原子和1-3个N原子的单环芳基,它可被至少一个选自Hal、A或OA的取代基取代。在最优选实施例中,Het1表示吡啶基,它可被至少一个选自Hal、A或OA的取代基一取代或二取代。高度优选的是,Het1表示吡啶基,它可被至少一个Hal或A的取代基一取代或二取代。应当理解,本发明任何基团中Het的相应含义是各自独立的。
杂芳基在“Het2”的意义上较佳为表示具有2-5个碳原子和1-3个N、O和/或S原子的任选地取代的饱和、不饱和或芳香族单环的5-6元杂环。在更优选的本发明实施例中,Het2表示具有2-5个碳原子和1-2个N、O和/或S原子的饱和、不饱和或芳香族单环的5-6元杂环。
术语“卤素”、“卤原子”、“卤素取代基”或“Hal”在本发明的意义上表示一个或几个氟(F)、溴(Br)、氯(Cl)或碘(I)原子。术语“二卤”、“三卤”和“全卤”分别涉及两个、三个和四个取代基,每个取代基可各自独立地选自F,Cl,Br或I。卤素较佳为表示F、Cl或Br原子。F和Cl是特别优选的,特别是当卤素取代在烷基(卤代烷基)或烷氧基(例如CF3和CF3O)上时。应当理解,本发明任何基团中“Hal”的相应含义是各自独立的。
在某些实施例中,本发明提供通式I化合物,式中W1、W2、W3、W4各自独立地是N或者CH,但条件是W1、W2、W3或者W4中只有一个是N。换言之,W1或W2或W3或W4是N,其余三个基团是CH。在某些实施例中,W1是N,且W2、W3、W4是CH。在某些实施例中,W2是N,且W1、W3、W4是CH。
在某些实施例中,R1是Ar。在某些实施例中,R1是Het1。
在某些实施例中,R1是苯基、萘基、环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基、环辛基、[3.3.0]二环辛基、[4.3.0]二环壬基、[4.4.0]二环癸基、[2.2.2]二环辛基、芴基、茚满基、四氢萘基、吖啶基、氮杂环辛四烯基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并噻吩呋喃基(benzothiofuranyl)、苯并噻吩苯基(benzothiophenyl)、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑、苯并咪唑啉、咔唑基、NH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、假吲哚基(indolenyl)、二氢吲哚基、中氮茚基(indolizinyl)、吲哚基、3H-吲哚基、异二氢吲哚、异假吲哚基(isoindolenyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、苯硫基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、氧杂环丁烷基、氮杂环丁烷基、或呫吨基;每个所述基团是任选地取代的。
在各种实施中例,R1是苯基或吡啶基,每个所述基团是任选地取代的。
在各种实施中例,R1是
在某些实施例中,R2是H。在某些实施例中,R2是具有1-10个碳原子的无支链的或有支链的烷基,其中1-7个H原子可以相互独立地被Hal所替代。
在某些实施例中,R3是H。在某些实施例中,R3是-(CH2)p-NR4R5。在某些实施例中,R3是-CH2-NR4R5。
在某些实施例中,R3是H、
在某些实施例中,本发明的R4、R5基团是A,或者两者一起表示-(CY2)q-。在某些实施例中,R4、R5一起表示-(CY2)q-。在某些实施例中是-(CH2)q-。在某些实施例中,R4、R5一起表示-(CY2)3-。
在本发明的另一方面,Y表示H或A。应当理解,本发明任何基团中“Y”的相应含义是各自独立的。
在某些实施例中,m是0或1。
在某些实施例中,n是1或2。
在某些实施例中,p是1或2。在某些实施例中,p是1。应当理解,本发明任何基团中“p”的相应含义是各自独立的。
在某些实施例中,q是3、4或5。在某些实施例中,q是3或4。在某些实施例中,q是3。
因此,本发明的主题涉及通式(I)化合物,其中至少一个上述基团具有上面标明的意义,特别是实现以上描述的较佳实施例。在通式(I)、其子结构式或其上面的其他残基的任何实施例中没有更详细标明的基团应当理解为具有为达到本发明目的而在此处公开的通式(I)中表示的含义。这意味着上述基团可采取指派给它们的所有含义,如上面或下面包括任何优选实施方案所描述的,而没有被束缚于其上,并独立地出现于另外的特定情况下。应当特别理解的是,某个基团的每个实施例可以与一个或几个其它基团的每个实施例相结合。
在某些实施例中,本发明提供通式(I’)所示的化合物:
式中,W1、W2、W3、W4、R1、R2、R3和m具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(I”)所示的化合物:
式中,W1、W2、W3、W4、R1、R2、R3和m具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(II)所示的化合物:
式中,R1、R2、R3和m具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(III)所示的化合物:
式中,R1、R2、R3和m具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(III-a)所示的化合物:
式中,R1、R2、R3和m具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(IV)所示的化合物:
式中,W1、W2、W3、W4、R1、R3和n具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(V)所示的化合物:
式中,W1、W2、W3、W4、R1、R3和n具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(VI)所示的化合物:
式中,W1、W2、W3、W4、R1、R4和R5具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(VII)所示的化合物:
式中,W1、W2、W3、W4、R1、R4和R5具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(VIII)所示的化合物:
式中,R4、R5和Ar具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义;
和/或其生理学上可接受的盐。
在某些实施例中,本发明提供通式(VIII)所示的化合物,式中R4是甲基且R5是H。在某些实施例中,本发明提供通式(VIII)所示的化合物,式中R4和R5以及氮一起形成氮杂环丁烷环。
在某些实施例中,本发明提供通式(VIII)所示的化合物,式中Ar是苯基,所述苯基被1或2个卤素或卤代烷基取代。在某些实施例中,本发明提供通式(VIII)所示的化合物,式中Ar是苯基,所述苯基被1或2个Cl或CF3取代。在某些实施例中,本发明提供通式(VIII)所示的化合物,式中Ar是苯基,所述苯基被1个Cl和1个CF3取代。在某些实施例中,本发明提供通式(VIII)所示的化合物,式中Ar是苯基,所述苯基被2个CF3取代。
在某些实施例中,本发明提供通式(VIII)所示的化合物,式中R4是甲基且R5是H。在另一实施例中,Ar是苯基,所述苯基被1或2个卤素或卤代烷基取代。在另一实施例中,本发明提供通式(VIII)所示的化合物,式中Ar是苯基,所述苯基的对位被Cl取代且间位被CF3取代。
在某些实施例中,W1、W2、W3、W4、R1、R2、R3、R4、R5和m各自具有上面标明的的意义以及在上面和此处实施例、类别及子类中单独或组合地描述的意义。
在某些实施例中,本发明提供实施例中描述的化合物1-76。
通式(I)所示的氮杂喹唑啉羧酰胺衍生物及其制备用的起始物料通过各自已知的方法进行制备,如文献(例如标准出版物,如Houben-Weyl,Methoden der organischenChemie[Methods of Organic Chemistry],Georg-Thieme-Verlag,Stuttgart)中所记载和/或本领域技术人员已知的,即在已知的和适合所述反应的反应条件下进行制备。
也可使用它们已知的变体,此处不作详述。若有需要的话,可以原位形成起始物料,让它们在粗反应混合物中保持未分离状态,但立即将它们转化为本发明的化合物。另一方面,可以逐步进行反应。
反应通常在在惰性溶剂中进行。合适的惰性溶剂例如是烃类,如己烷、石油醚、苯、甲苯或二甲苯;氯化烃类,如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇类,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚类,如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;乙二醇醚类,如乙二醇单甲醚或单乙醚、乙二醇二甲醚(二甘醇二甲醚);酮类,如丙酮或丁酮;酰胺类,如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈类,如乙腈;亚砜类,如二甲亚砜(DMSO);二硫化碳;羧酸类,如甲酸、乙酸或三氟乙酸(TFA);硝基化合物,如硝基甲烷或硝基苯;酯类,如乙酸乙酯;或所述溶剂的混合物。特别优选的是DMF、TFA、水、THF、叔丁醇、叔戊醇、三乙胺或二噁烷。
根据所用条件,反应时间在几分钟和14天之间,反应温度在-30℃和140℃之间,通常在-10℃和130℃之间,特别适宜的是在0℃和100℃之间。
本发明还涉及制备通式(I)化合物的方法,包括如下步骤:
(a)使通式(IX)化合物
其中W1、W2、W3和W4具有上面指明的含义,
与通式(X)化合物反应,
其中R1、R2、R3和m具有上面指明的含义,
得到通式(I)化合物,
其中W1、W2、W3、W4、R1、R2、R3和m具有上面指明的含义,
并任选地
(b)将通式(I)化合物的碱或酸转换为它们的一种盐。
通式(I)所示的氮杂喹唑啉羧酰胺衍生物可以通过上述路径获得。起始物料,包括通式(IX)和(X)化合物,对本领域技术人员通常是已知的,或者它们可通过已知的方法制备。因此,通式(IX)和(X)的任何化合物可以被纯化为中间产物并用作制备通式(I)化合物的起始物料。
在上述方法的最后步骤中,任选地提供通式(I)的化合物的盐。本发明的化合物可以非盐的最终形式加以使用,另一方面,本发明还包括这些化合物以其药学上可接受的盐的形式加以使用,这些药学上可接受的盐可用本领域已知的方法从各种有机和无机酸和碱制备得到。大多数情况下,本发明化合物的药学上可接受的盐主要通过常规方法制备。如果本发明化合物包含羧基,可通过该化合物与合适的碱反应形成其合适的盐,即得到相应的碱加成盐。这样的碱为,例如,碱金属氢氧化物(如氢氧化钾、氢氧化钠和氢氧化锂)、碱土金属氢氧化物(如氢氧化钡和氢氧化钙)和碱金属醇盐(如乙醇钾和丙醇钠),及各种有机碱,如哌啶、二乙醇胺和N-甲基谷氨酰胺。同样也包括本发明化合物的铝盐。对于本发明的大多数化合物,较佳的是这些化合物可与药学上可接受的有机酸或无机酸反应生成酸加成盐类,这些酸的实例如卤化氢,如氯化氢、溴化氢或碘化氢;其它矿酸及其相应的盐类,如硫酸盐、硝酸盐或磷酸盐等,以及烷基或单芳基磺酸盐,如乙磺酸盐、对甲苯磺酸盐和苯磺酸盐,以及其它有机酸及其相应的盐类,如醋酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、枸橼酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此本发明的化合物的药学上可接受的酸加成盐包括:醋酸盐、己二酸盐、海藻酸盐、精氨酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、硫酸氢盐、亚硫酸氢盐、氢溴酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、盐酸盐、氯苯甲酸盐、枸橼酸盐、环戊基丙酸盐、葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙基磺酸盐、富马酸盐、半乳糖二酸盐(源于粘酸)、半乳糖醛酸盐、葡萄糖庚酸盐、葡萄糖酸、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、单硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、碘盐、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲烷磺酸盐、甲基苯甲酸盐、磷酸氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、苯乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但是这些实例并不表示对本发明的限制。
关于上面的描述,可以看到,本说明书中的术语“药学上可接受的盐”和“生理学上可接受的盐”是可以互换的,在本文中用来表示包含本发明化合物的一种盐形式的活性成分,特别是如果这种盐形式给活性成分带来与该活性成分游离形式相比改善的药代动力学性质。活性成分的药学上可接受的盐形式还可第一次给这种活性成分带来期望的药代动力学性质,甚至可对此活性成分体内治疗效应的药效学具有积极影响。
本发明的目的也是通式(I)所示的化合物和/或其生理学上可接受的盐在调节,优选地抑制p70S6激酶活性中的用途。术语“调节”表示基于特定的本发明化合物的作用而使p70S6K介导的信号传导发生任何的改变,本发明化合物能够与靶p70S6K相互作用,使得识别、结合和抑制成为可能。术语“抑制”表示基于特定的本发明化合物的作用而使p70S6K活性发生任何的减低,本发明化合物能够与靶p70S6K相互作用,使得识别、结合和阻断成为可能。化合物的特征是具有与至少一种针对p70S6K高的亲和力,确保可靠的结合和阻断p70S6K活性。如果合适的话,这也适用于靶Akt。较佳的是,物质是p70S6K特异性的,以保证对p70S6K靶的唯一和直接识别。更佳的是,物质是双特异性的,以保证对p70S6K靶和Akt靶的唯一和直接识别。在本发明的上下文中,术语“识别”–非限制性地-涉及在特定化合物和靶之间的任何类别的相互作用,特别是共价或非共价结合或缔合,例如共价键、亲水/疏水相互作用、范德华力、离子对、氢键、配体-受体相互作用等等。这样的缔合也可以包含其他分子(例如肽、蛋白质或核苷酸序列)的存在。本发明的相互作用的特征是高亲和力、高选择性以及与其他靶分子有极小的甚至没有交叉反应,从而排除了对治疗受试者产生不健康的和有害的作用。
本发明的一个优选目的涉及抑制p70S6激酶的方法,其中能够表达p70S6激酶的系统,优选地表达p70S6激酶的系统,与至少一种本发明通式(I)所示的化合物和/或其生理学上可接受的盐在抑制p70S6激酶的条件下接触。在本发明的范围内较佳的是细胞系统。所述细胞系统被定义为任何受试者,只要该受试者包含细胞。因此,细胞系统可以选自单细胞、细胞培养物、组织、器官和动物。抑制p70S6激酶的方法较佳地在体外进行。本说明书上文有关通式(I)化合物(包括其任何优选实施例)的教导是有效的和适用的,当在抑制p70S6激酶的方法中不限于通式(I)化合物及其盐。
根据本发明的化合物优选地表现出有利的生物学活性,这在细胞培养基试验,例如本文或现有技术所描述的试验中容易地被证实。在这样的试验中,根据本发明的化合物优选地显示出并导致抑制效果。本发明的化合物的EC50值在10nM至25μM的范围内。优选的是,本发明的化合物具有活性,以EC50标准表示,其中EC50是5μM或以下,优选1μM或以下,更优选为0.5μM或以下,最优选小于0.1μM。“EC50”是化合物产生最大可能反应的一半时该化合物的有效浓度。
本发明的方法可以在体外或体内进行。可在研究和临床应用的过程中用体外试验测定对用本发明化合物治疗具体细胞的敏感性。通常混合培育细胞培养物与各种浓度的本发明化合物足够时间,其时间使活性药物得以调节p70S6K活性,培养时间常介于1小时与1周之间。可用活检样品或细胞系的培养细胞进行体外处理。在本发明的一优选方面,刺激卵泡细胞成熟。计算处理后剩余的存活细胞数目并作进一步处理。
宿主或患者可属于哺乳动物,如灵长类动物,具体是人;啮齿动物,包括小鼠、大鼠和仓鼠;兔,马,牛,狗,猫等。供实验研究的感兴趣动物模型可提供治疗人类疾病的模型。
为了鉴定信号转导通路和检测各种信号转导通路之间的相互作用,许多科学家开发了适当的模型或模型系统,例如细胞培养模型和转基因动物模型。为了检测信号转导级联反应所处的某些阶段,可采用相互作用的化合物来调节信号。可将本发明化合物用作试剂来检测动物模型和/或细胞培养模型或本申请书中所提及临床疾病中的p70S6K依赖性信号转导通路状况。
本说明书上述段落描述的用途可在体外或体内模型中进行。通过本说明书上下文描述的技术监测所述调节。体外用途较佳地用在患有过度增殖性疾病的人样本。通过测试多种特异性化合物和/或其衍生物就能选择出最适合人患者治疗的活性成分。所选衍生物的体内剂量率宜与对p70S6K的易感性和/或考虑到体外(试验)数据而定的患者疾病的严重程度相匹配,从而显著提高治疗效果。此外,本说明书以下涉及通式(1)化合物及其衍生物在制备预防、或治疗和/或控制疾病进程的药物上的用途的教导是有效的和适用的,如果看起来合理,可不限于本发明化合物调节p70S6K活性的用途。
如本文中所讨论的,PI3K信号通路与各种疾病(优选肿瘤学的疾病)相关联。因此,本发明的化合物通过与所述信号传导通路的一或多个通路相互作用而可用于预防和/或治疗依赖于所述信号通路的疾病。因此,本发明涉及本发明的化合物用作本文描述的信号通路,优选为PI3K介导的信号通路的调节剂,优选用作抑制剂。具体地,本发明涉及本发明化合物在制备用于治疗以下疾病的药物中的用途:哺乳动物中与p70S6K的过强活性相关联的过度增殖性疾病以及由p70S6K级联介导的疾病、或者由异常增殖介导的疾病,如癌症和炎症。
本发明也涉及含有至少一种本发明化合物和/或其药学上可用的衍生物、盐、溶剂化物和立体异构体,包括它们的各种比例混合物,的药物。较佳地,本发明涉及包含至少一种本发明化合物和/或其生理学上可接受的盐的药物。
本发明意义的“药物”是药物领域的任何药剂,包括一或多种通式(I)化合物或其制剂(例如药物组合物或药物制剂),可用于预防、治疗、跟进或治疗后调养患有与p70S6K活性相关的疾病的患者,所述患者至少暂时地显示整体病况或患者机体个别部分的病理改变。
因此,本发明还涉及包含至少一种本发明的通式(I)化合物和/或其生理上可接受的盐作为活性化合物,以及药学上可耐受的佐剂和/或赋形剂的药物组合物。应当理解,本发明的化合物以有效量提供。
本发明意义的“佐剂”表示当同时、前后或依次给予时,能促进、增强或改善本发明的活性成分的特异性反应的任何物质。已知的注射液佐剂例如有:铝组合物,如氢氧化铝或磷酸铝;皂甙类,如QS21;胞壁酰二肽或胞壁酰三肽;蛋白质,如γ-干扰素或TNF;MF59;角鲨烯或多元醇。
此外,活性成分可以单独给予或者与其他治疗一起联用。在药物组合物中使用根据本发明的一或多化合物可取得增效作用,即通式(I)化合物与作为活性成分的至少一种其他药剂联用,该其他药剂可以是通式(I)的另一种化合物或者具有不同结构骨架的化合物。该些活性成分可以同时或依次使用。本发明还涉及用于抑制哺乳动物中异常细胞生长/癌症的化合物或药物组合物,其包含一定量的本发明化合物或其可药用盐或溶剂化物或前体药物以及一定量的另外的抗癌治疗药物,其中所述化合物、盐、溶剂化物或前体药物的量与化学治疗剂的量一起对抑制异常细胞生长/癌症是有效的。本发明的化合物适合与已知的抗癌药物联用。
许多抗癌治疗药物目前在本领域内中是已知的。在一个优选实施方案中,其它活性药物成分是抗癌治疗药物,所述抗癌治疗药物是选自以下的化学治疗剂:有丝分裂抑制剂、烷化剂、抗代谢药、嵌入抗生素(intercalating antibiotics)、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物学应答调节剂、抗激素、血管生成抑制剂和抗雄激素。在另一个优选实施方案中,所述抗癌治疗药物是选自以下的抗体:贝伐单抗、CD40-特异性抗体、chTNT-1/B、地舒单抗、扎木单抗、IGF1R-特异性抗体、林妥珠单抗、依决洛单抗、WXG250、利妥昔单抗、替西木单抗、曲妥单抗和西妥昔单抗。在又一个优选实施方案中,所述抗癌治疗药物是另一种蛋白激酶的抑制剂,所述蛋白激酶诸如Akt、Axl、Aurora A、Aurora B、dyrk2、epha2、fgfr3、igf1r、IKK2、JNK3、Vegfr1、Vegfr2、Vegfr3(也称为Flt-4)、KDR、MEK、MET、Plk1、RSK1、Src、TrkA、Zap70、cKit、bRaf、EGFR、Jak2、PI3K、NPM-Alk、c-Abl、BTK、FAK、PDGFR、TAK1、LimK、Flt-3、PDK1和Erk。其它抗癌药物已为本领域技术人员所知,可与本发明的化合物一起使用。
本发明同时还涉及组件(药盒),其由分开包装的有效量的本发明化合物和/或其药学上可接受的盐、衍生物、溶剂化物和立体异构体,包括它们的各种比例混合物,以及有效量的其他活性成分所组成。该药盒包含合适的容器,例如,盒子、各种瓶子、袋子或安瓿。例如,该药盒可包含分置的安瓿,每个安瓿装有溶解形式或冻干形式的有效量本发明化合物和/或其药学上可接受的盐、衍生物、溶剂化物和立体异构体,包括它们的各种比例混合物,和有效量的其他药物治疗活性化合物。
药物制剂可适应于经所需的适当方法给药,例如通过口服(包括口腔或舌下)、直肠、鼻腔、局部(包括口腔、舌下或透皮)、阴道或非肠道(包括皮下、肌肉注射、静脉注射或皮内)方法。这种制剂可以用药学领域的专业人员已知的各种方法制备,例如,将有效成分与赋形剂或佐剂混合。
本发明的药物组合物以合适剂量用已知的方法采用常规药物工程用的固体或液体运载体、稀释剂和/或添加剂来制备。为了制备单位剂量,与活性成分混合的赋形剂的量因所治疗个体和给药方式而异。合适的赋形剂包括适合不同给药途径的有机或无机物质,例如肠内(如口服)、肠胃外或局部给药,这些有机或无机物质不会与通式(I)化合物或其盐反应。此种类型赋形剂的例子有:水、植物油、苯甲醇类、烷撑二醇、聚乙二醇、甘油三乙酸盐、明胶、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石粉和凡士林。
适合于口服给药的药物制剂可作为独立的单元给药,例如,胶囊或片剂;粉剂或颗粒剂;在水和非水液体中的溶液或悬浮液;食用泡沫或泡沫食品;或水包油型液体乳剂与油包水型液体乳剂。
适合于非肠道给药的药物制剂,包括水和非水无菌注射液,由抗氧化剂、缓冲液、抑菌剂和溶质组成,通过这一手段使制剂与受治疗者的血液呈现等渗;还包括水和非水无菌悬浮液,其中可包括悬浮介质和增稠剂。该制剂可以装在单剂量或多剂量容器中给药,例如密封安瓿和小瓶,并以冷冻干燥(冻干)状态储存,这样只需要在临用前立即加入无菌载体液体,例如注射用水。注射液和悬浮液按照处方可以从无菌粉、颗粒剂和片剂制备。
不用说,除上述特别提到的成分以外,这些制剂也可包括关于特定制剂类型的本技术领域人员通用的其他物质,因此,例如,适合口服给药的制剂可以包含芳香剂。
在本发明的一优选实施例中,药物组合物适合于口服。制剂可以被消灭菌或可以包含佐剂,如载体蛋白质(例如血清白蛋白)、润滑剂、防腐剂、稳定剂、填充剂、螯合剂、抗氧化剂、溶剂、结合剂、悬浮剂、湿润剂、乳化剂、盐(影响渗透压的盐)、缓冲物质、着色剂、芳香剂以及一或多种其他活性物质(例如一或多种维生素)。添加剂已为本领域所知,它们可用于各种不同的制剂中。
因此,本发明还涉及一种药物组合物,其包含作为活性药物成分的至少一种本发明通式(I)化合物和/或其生理学上可接受的盐以及药学上耐受的佐剂,所述药物组合物任选地与至少一种其他活性药物成分联用。两种药物活性成分尤其以有效量提供。说明书上述有关给药途径和联用产品的教导是有效的和适用的,如果看起来合理,可不限于两个特征的组合。
术语“有效量”或“有效剂量”或“剂量”在本说明书中可互换使用,指对疾病或病理有预防或治疗作用的药学化合物的量,即能引起组织、系统、动物或人发生研究人员或医生所寻求或期望的生物或医学反应。“预防作用”是减低疾病发展甚至防止疾病发作的可能性。“治疗相关作用”指某程度上解除一种或一种以上疾病症状,或部分或完全地将与疾病或病理相关的或导致疾病或病理改变的一种或一种以上或所有的生理或生化参数逆转成正常状态。此外,用语“治疗有效量”表示与未接受此量的相应患者相比,该量产生如下结果:治疗改善,治愈,预防或消除疾病、综合征、疾病状况、患者主诉、病变或副作用或也减缓疾病、主诉或病变的进程。用语“治疗有效量”也涵盖了对增进正常生理功能有效的量。
本发明的药物组合物的给药剂量或剂量范围要足够高,以达到所期望的减轻上述疾病(例如癌症和炎症)的预防或治疗作用。应当理解,任一具体人的特定剂量水平、频率和给药周期取决于多种因素,包括,所选用具体化合物的活性、年龄、体重、健康状况、性别、饮食状态、给药时间和途径、排泄率、药物组合和需要治疗的具体病情及其严重程度。采用已知的方式和方法,本领域技术人员按常规实验可确定准确剂量。本说明书上文的教导是有效的和适用的,如果合理的话,不限于包含通式(I)化合物的药物组合物。
药物制剂可以剂量单位的形式给药,剂量单位由每单位剂量的活性成分的预设量组成。制剂中活性成分的预防浓度或治疗浓度可以在0.1至100wt%之间变化。较佳地,通式(I)化合物或其药学上可接受的盐的给药剂量可以是大约0.5至1000mg,优选是1mg至700mg,尤其是优选5mg至100mg。通常,这样的剂量范围对于每日总给药量是适合的。换言之,日剂量较佳地是大约0.02至100mg/kg体重。但是,每个病人具体的剂量取决于本说明书上文已经描述的许多因素(例如所治疗的病情、给药方式和病人年龄、体重和身体状况)。优选的剂量单位制剂包括如上所述活性成分的每日剂量或部分剂量,或相应的其中一部分。此外,这种类型的药物制剂可以用药学领域的专业人员普遍熟知的方法加以制备。
虽然本发明化合物的治疗有效量最终由主治医生或兽医考虑多种因素后确定(例如,动物的年龄和体重、需要治疗的准确病情及其严重程度、制剂的性质和给药方法),但本发明化合物用于治疗肿瘤生长(例如结肠或乳腺癌)的有效剂量一般在每日0.1至100mg/kg受治疗者(哺乳动物)体重的范围内,特别是通常在每日1到10mg/kg体重的范围内。因此,体重70kg的成年哺乳动物每日的实际剂量通常在70至700mg之间,这个剂量可以作为单一剂量每天服用,通常也可以分成部分剂量每天多次服用(例如,二、三、四、五、六次),使每日总剂量保持相同。盐类或溶剂化物或其生理功能衍生物的有效剂量可确定为化合物本身有效剂量的部分。可以设想,类似的剂量适用于治疗上文提及的其它症状。
本发明的药物组合物可作为人医学和兽医学用药。根据本发明,通式(I)化合物和/或其生理学上可接受的盐适合用于预防性或或治疗性治疗和/或监测由p70S6K活性引致、介导和/或蔓延的疾病。尤其优选的是,该疾病是过度增殖性疾病、癌症、转移、肿瘤、血管生成病症、肿瘤血管生成、良性增生、血管瘤、神经胶质瘤、黑素瘤、卡波氏肉瘤、血管发生或血管生成相关性前列腺疾病、炎症、胰腺炎、视网膜病变、早产儿视网膜病变、糖尿病性视网膜病、糖尿病、疼痛、再狭窄、牛皮癣、湿疹、硬皮病和年龄相关性黄斑变性。应当理解,化合物的宿主包括在本发明的保护范围内。
优选的是用于治疗以下疾病:癌症,例如脑癌、肺癌、结肠癌、表皮样癌、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、乳腺癌、头癌、颈癌、肾癌、肾的癌、肝癌、卵巢癌、前列腺癌、结直肠癌、子宫癌、直肠癌、食管癌、睾丸癌、妇科癌、甲状腺癌、黑素瘤、恶性血液病,诸如急性髓性白血病、多发性骨髓瘤、慢性髓性白血病、骨髓细胞白血病、神经胶质瘤、卡波西肉瘤,或其它任何类型的实体或液体肿瘤。更优选地,治疗的癌症选自乳腺癌、结直肠癌、肺癌、前列腺癌或胰腺癌、或成胶质细胞瘤。
采用本发明的化合物治疗的示范性疾病包括:前列腺癌,甲状腺癌,肝癌,肺癌,乳腺癌,结肠癌,前列腺癌,垂体瘤,膀胱癌,乳腺癌,结肠癌(例如结肠直肠癌如结肠腺癌和结肠腺瘤),肾癌,表皮癌,肝癌,肺癌,例如上述器官的腺癌,小细胞肺癌和非小细胞肺癌,食道癌,胆囊癌,卵巢癌,胰腺癌如外分泌胰腺癌,胃癌,子宫颈癌,子宫内膜癌,甲状腺癌,前列腺癌,或皮肤癌(例如鳞状细胞癌);淋巴系统的造血肿瘤(例如白血病、急性淋巴细胞性白血病、慢性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛细胞淋巴瘤或伯基特淋巴瘤);骨髓系统的造血肿瘤(例如白血病、急性和慢性骨髓性白血病、骨髓增生综合征、骨髓增生异常综合征或早幼粒细胞白血病);多发性骨髓瘤;甲状腺滤泡癌;源自间叶细胞的肿瘤(例如纤维肉瘤和眼眶横纹肌肉瘤);中枢或周围神经系统肿瘤(例如星细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤);黑素瘤;精原细胞瘤;畸胎癌;骨肉瘤;着色性干皮病;角化棘皮瘤;甲状腺滤泡状癌或卡波氏肉瘤。
在某些实施方案中,所述疾病是膀胱癌,乳腺癌,宫颈癌,结肠癌,表皮癌,胆囊癌,肾癌,肝癌,肺癌,垂体瘤,食道癌,卵巢癌,胰腺癌,前列腺癌,胃癌,甲状腺癌,白血病,B细胞淋巴瘤,T细胞淋巴瘤,何杰金氏淋巴瘤,非何杰金氏淋巴瘤,毛细胞淋巴瘤,伯基特淋巴瘤,急性和慢性髓细胞性白血病,骨髓增生综合征,骨髓增生异常综合征,髓细胞性白血病;多发性骨髓瘤,甲状腺滤泡癌;星细胞瘤,成神经细胞瘤,神经胶质瘤,神经鞘瘤,黑素瘤或卡波氏肉瘤。
在某些实施方案中,所述疾病是多发性骨髓瘤,骨髓增生性疾病,子宫内膜癌,前列腺癌,膀胱癌,肺癌,卵巢癌,乳腺癌,胃癌,结肠直肠癌,以及口腔鳞状细胞癌。在某些实施例中,所述疾病是多发性骨髓瘤,膀胱癌,子宫颈癌,前列腺癌,甲状腺癌,肺癌,乳腺癌,或结肠癌。
进一步优选的是用于治疗哺乳动物中与血管发生或血管生成有关的疾病,其包含给予治疗有效量的本发明化合物或其可药用盐、前体药物或水合物以及可药用的载体。在一个实施方案中,本发明的化合物或药物组合物用于治疗以下组内的疾病:肿瘤血管生成;慢性炎性疾病,如类风湿性关节炎、炎性肠病、动脉粥样硬化;皮肤疾病,如牛皮癣、湿疹、硬皮病;代谢性疾病,例如糖尿病、肥胖症、代谢综合征、胰岛素抵抗、高血糖、高氨基酸血症、高脂血症、糖尿病性视网膜病、早产儿视网膜病变;与年龄相关性黄斑变性。
本发明还涉及通式(I)化合物和/或其生理学上可接受的盐在预防性或治疗性治疗和/或监测由p70S6活性引致、介导和/或蔓延的疾病的用途。本发明还涉及通式(I)化合物和/或其生理学上可接受的盐在制备用于预防性或治疗性治疗和/或监测由p70S6活性引致、介导和/或蔓延的疾病的药物中的用途。通式(I)化合物和/或其生理学上可接受的盐也可以用作制备其他药物活性成分的中间体。药物较佳地以非化学方式制备,例如将活性成分与至少一种固体、液体和/或半液体载体或赋形剂组合,任选地在合适的剂型中掺合一或多种其他活性物质。
本发明的另一个目的是本发明的通式(I)化合物和/或其生理学上可接受的盐,它们用于预防性或治疗性治疗和/或监测由p70S6K活性引致、介导和/或蔓延的疾病。本发明另一优选目的涉及本发明通式(I)所示的化合物和/或其生理学上可接受的盐用于预防性或治疗性治疗和/或监测过度增殖性疾病。本说明书上文涉及通式(1)化合物及其优选实施例的教导是有效的和适用的,不限于通式(1)化合物及其盐用于预防性或治疗性治疗和/或监测过度增殖性疾病。
本发明通式(I)所示的化合物可在发病前或后给予一次或多次作为治疗。本发明的上述化合物和医学产品特别用于治疗性治疗。治疗相关作用指某程度上解除一种或多种疾病症状,或部分或完全地将与疾病或病理相关的或导致疾病或病理改变的一种或多种生理或生化参数逆转成正常状态。假如化合物以不同的时间间隔给予,监测可被认为是一种治疗,以增强应答和完全根除疾病病原体和/或症状。可以施加同一种或不同种化合物。也可以使用药物来减低发展疾病或者甚至预先防止与p70S6K活性相关的病症出现,或者治疗出现的或持续有的病症。本发明涉及的疾病较佳地是过度增殖性疾病。
在本发明的意义中,如果受试者拥有上述生理或病理状况的前置条件,例如家族性倾向、基因缺陷、或者曾经有过病史,给予预防性治疗是可取的。
本发明的另一个目的是提供治疗由p70S6K活性引致、介导和/或蔓延的疾病的方法,其中向有需要此种治疗的哺乳动物给予至少一种本发明的通式(I)化合物和/或其生理学上可接受的盐。本发明的另一个优选目的是提供治疗过度增殖性疾病的方法,其中向有需要此种治疗的哺乳动物给予至少一种本发明的通式(I)化合物和/或其生理学上可接受的盐。所述化合物优选地以如上所述的有效量提供。较佳的治疗是口服给药。
在另一个优选的方面中,治疗哺乳动物的癌症的方法包括给予所述哺乳动物一定量的本发明化合物,并与放射疗法联用,其中所述化合物的量与放射疗法联用能有效地治疗哺乳动物的癌症。施用放射疗法的技术是本领域已知的,并且这些技术可以与本文描述的疗法联用。根据如本文所述的确定化合物的有效量、剂量和给药路径的方法可以确定在组合疗法中本发明化合物的量和给药方式。据信,本发明化合物可以使异常细胞对杀死和/或抑制这些细胞生长的辐射治疗更敏感。因此,本发明涉及一种使接受辐射治疗的哺乳动物的异常细胞敏感化的方法,包括向哺乳动物施加一定量的本发明化合物,所述量能有效地敏感化接受辐射治疗的异常细胞。
本发明的另一个方面是提供一种用于抑制哺乳动物的异常细胞生长的方法,其包括给予一定量的本发明化合物或其同位素标记的衍生物,以及一定量的一种或多种选自抗血管生成剂、信号转导抑制剂和抗增殖剂。
本申请公开的通式I所示的化合物可与包括抗癌药物在内的已知的治疗剂联用。此处所用的术语“抗癌药物”涉及给予癌症患者用于治疗癌症的任何药物。
以上定义的抗癌治疗可作为单一疗法应用,或者除了本文公开的此处公开的通式I所示的化合物之外可包括常规手术或放射疗法或药物治疗。这种药物治疗例如化疗或靶向治疗,可包括一种或多种,但是优选地为一种以下抗肿瘤药物:
烷化剂:例如六甲密胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥、环磷酰胺、氮烯唑胺、异环磷酰胺、甲磺丙胺、洛莫司汀、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、雷莫司汀、替莫唑胺、噻替派、苏消安、二氯甲基二乙胺、卡波醌、阿帕齐醌、福莫司汀、葡磷酰胺、帕利伐米、哌血生、曲磷胺、尿啼陡氮芥、TH-3024、VAL-0834;
铂化合物:例如卡铂、顺铂、依铂、米铂水合物、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;洛铂、奈达铂、吡铂、赛特铂;
DNA改性剂:例如氨柔比星、蒽双咪腙、地西他滨、米托蒽醌、甲基苄肼、曲贝替定、氯法拉滨;安吖啶、溴他里辛、匹杉琼、laromustine1,3;
拓扑异构酶抑制剂:例如依托泊苷、伊立替康、雷佐生、索布佐生、替尼泊苷、托泊替康;氨萘非特、贝洛替、依利醋铵、伏利拉辛(voreloxin);
微管改性剂:例如卡巴他赛、多西他赛、艾日布尔、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁;康普瑞汀A4前体药物(fosbretabulin)、替司他赛;
抗代谢药物:例如天冬酰胺酶3、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟;脱氧氟尿苷、艾西拉滨、雷替曲塞、沙帕他滨、替加氟2,3、三甲曲沙;
抗癌抗生素:例如博来霉素,更生霉素、阿霉素、表阿霉素、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地辛、链佐星、戊柔比星、净司他丁、佐柔比星、柔红霉素、普卡霉素;阿柔比星、派来霉素、吡柔比星;
激素/拮抗剂:例如阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡普睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙、甲睾酮、氟他胺、氟维司群、戈舍瑞林、组氨瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺激素阿尔法、托瑞米芬、曲洛司坦、曲普瑞林、二乙基己烯雌酚;阿考比芬、达那唑、洛瑞林、环硫雄醇、orteronel、恩杂鲁胺1,3;
芳香酶抑制剂:例如氨基格鲁米特、阿那曲唑、依西美坦、法倔、来曲唑、睾内酯、福美坦;
小分子激酶抑制剂:例如克唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞格非尼、鲁索利替尼、索拉非尼、舒尼替尼、凡德他尼、维罗非尼、博舒替尼、吉非替尼、阿西替尼、阿法替尼、alisertib、达拉菲尼、达可替尼、dinaciclib、多韦替尼、恩扎妥林、尼达尼布、乐伐替尼、利尼伐尼、linsitinib、马赛替尼、米哚妥林、莫特塞尼、来那替尼(neratinib)、orantinib、哌立福辛、普纳替尼、拉多替尼、rigosertib、替批法尼、tivantinib、tivozanib、曲美替尼、pimasertib、丙氨酸布立尼布、西地尼布、阿帕替尼、卡波替尼S-苹果酸盐1,3、依鲁替尼1,3、埃克替尼4,buparlisib2,西帕替尼4,cobimetinib1,3,艾德利布1,3,fedratinib1,XL-6474
光敏剂:例如甲氧沙林3、吓吩姆钠、他拉泊芬、替莫泊芬;
抗体:例如阿仑单抗、贝西索单抗、贝伦妥单抗-维多汀、西妥昔单抗、迪诺塞麦、易普利单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、群司珠单抗、贝伐单抗2,3、卡妥索单抗、elotuzumab、依帕珠单抗、farletuzumab、mogamulizumab、necitumumab、尼妥珠单抗、奥奴珠单抗、ocaratuzumab、奥戈伏单抗、雷莫芦单抗、利妥木单抗、司妥昔单抗、托珠单抗、扎鲁木单抗、扎木单抗、马妥珠单抗、达妥珠单抗1,2,3、onartuzumab1,3、雷妥莫单抗1、tabalumab1,3,EMD-5257974,纳武单抗(nivolumab1,3);
细胞因子:例如阿地白介素、干扰素α2、干扰素α2a3、干扰素α2b2,3、西莫白介素、他索纳明、替西白介素、奥普瑞白介素1,3、重组白介素β-1a4;
药物轭合物:例如地尼白介素-毒素连接物、替伊莫单抗、碘苄胍1123、松龙苯芥、曲妥珠单抗-emtansine、雌莫司汀、吉妥珠单抗、奥唑米星、阿柏西普、cintredekinbesudotox、依多曲肽、奥英妥珠单抗、那莫单抗、莫奥珠单抗、锝(99mTc)阿西莫单抗、vintafolide1,3;
疫苗:例如前列腺癌疫苗(sipuleucel3)、维特斯朋3、emepepimut-S3、结肠癌疫苗(oncoVAX4)、rindopepimut3、troVax4、MGN-16014、MGN-17034;以及
其它药物:阿利维甲酸、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、蘑菇多糖、甲酪氨酸、米伐木肽、帕米磷酸、培加帕酶、喷司他丁、sipuleucel3、西佐糖、他米巴罗汀、替西莫司、沙利度胺、维A酸、维莫德吉、唑来膦酸、沙利度胺、伏立诺他、塞来考昔、西仑吉肽、恩替诺特、依他硝唑、ganetespib、idronoxil、iniparib、ixazomib、氯尼达明、尼莫唑、帕比司他、培瑞维A酸、plitidepsin、泊马度胺、procodazol、ridaforolimus、他喹莫德、telotristat、胸腺法新、替拉扎明、托多司他、trabedersen、乌苯美司、伐司朴达多、今又生(gendicine4)、溶链菌4、reolysin4、盐酸瑞他霉素1,3、trebananib2,3、维鲁利秦4、卡非佐米1,3,血管内皮抑制素4,immucothel4,贝利司他3,MGN-17034。
(1Prop.INN(建议采用的国际非专有名称);2Rec.INN(推荐采用的国际非专有名称);3USAN(美国采用的名称);4no INN(没有名称))。
有关本发明及其实施方式的上述教导是有效的和适用的,如果看起来合理,可不限于本发明的方法。
在本发明的范围内,首次提供了通式(I)所示的新的氮杂喹唑啉羧酰胺。因为在喹唑啉羧酰胺骨架上引入了杂环原子,所以本发明的p70S6K抑制剂与现有技术的化合物在结构上是明显不同的。本发明包括使用通式(I)化合物通过p70S6K来调节、调控和/或抑制PI3K的信号传导级联反应,而p70S6K是所述通路的成员。本发明的化合物有利地为诊断和/或治疗应答p70S6K信号转导和抑制而引起的任何疾病提供研究工具。
例如,本发明的化合物可在体外作为独特工具,以理解p70S6K的生物作用,包括评价被认为会影响p70S6K产生以及被p70S6K产生影响的许多因素。本发明的化合物也可以用于研发与p70S6K相互作用的其他化合物,这是因为本发明的化合物提供了有利于这种研发的重要的结构-活性关系(SAR)信息。
本发明的化合物是有效的且具有口服生物可利用度的选择性p70S6K抑制剂,解决了有关疾病进程特征的多种状况下有待解决的医学需要,特别是癌症和炎症。含有所述化合物的药物和药物组合物以及使用所述化合物治疗p70S6K介导的病症是有前景的一种新方法,可应用在广泛的治疗方法中,能直接和实时改善人或动物的健康状况。其效果对有效地治疗过度增殖性疾病特别有利,不论是单独使用或与其它治疗方案一起使用。
由于本发明的化合物对p70S6K具有令人惊讶的抑制活性,因此有利的是它们的给药剂量比其它效力小的或选择性差的现有抑制剂低,而仍然能够达到同样的或者甚至更好的所期望的生物作用。另外,这种剂量减低有利于产生较少的或者甚至没有医学副作用。此外,通式(I)化合物及其盐、异构体、互变异构体、对映体形式、非对映体、外消旋体、衍生物、前药和/或代谢物的特征是高特异性和稳定性、低制造成本和方便处理。这些特征构成能重复再现作用的基础,其中包括没有交叉反应,并且可靠安全地与靶结构相互作用。
本说明书引用的全部文献均纳入本发明的内容作为参考。
应当理解,本发明不限于本说明书所述的具体化合物、药物组合物、用途和方法,因为这些都可以改变。此外应当理解的是,本说明书所用的术语唯一的目的是描述具体实施方式而不意味着限制本发明的范围。本说明书包括所附权利要求书中所用的单数词汇,例如,“一个”或“这个”包括其等价复数,只要上下文中没有另外专门地指出。例如,本领域技术人员知道,提及“一个化合物”包括单个或多个化合物,进而可以是相同或不同的;或提及“一种方法”,包括多个等价步骤和方法。除非另有限定,本说明书中使用的全部技术和科学术语具有本发明所属技术领域的普通技术人员所通常理解的意义。
本发明要点的技术在本说明书中详细描述。没有详细描述的其他技术对应于已为本领域技术人员公知的已知标准方法,或者在所引用的文献、专利申请或标准文献中有详细描述。虽然在实践和测试本发明时可以采用此处描述的方法和材料,但下文仍然给出了合适的实施例。以下实施例仅作为示例给出,没有任何限制作用。在实施例中使用不含任何污染性(任何实践的场合)的标准试剂和缓冲液。构建实施例,它们不限于明确示出的各种特征组合,但是如果解决了本发明的问题,验证的特征可以不受限制地组合起来。同样地,任一权利要求的特征可与其它权利要求的一或多项中的特征组合起来。
下面的实施例中,“常规检测”表示:根据终产物的情况,如果必要的话加水,调节pH(如果必要)至2-10,用乙酸乙酯或二氯甲烷对混合物进行提取,相分离,有机相用硫酸钠干燥,蒸发,用硅胶或C-18色谱法和/或结晶法纯化。
在本申请中可能出现的某些缩写如下:
ACN | 乙腈 |
AcOH | 乙酸 |
AIBN | 偶氮二异丁腈 |
ATP | 三磷酸腺苷 |
b | 宽峰 |
Bop-Cl | 双(2-氧代-3-噁唑烷基)次磷酰氯 |
Conc. | 浓缩 |
d | 双峰 |
DCM | 二氯甲烷 |
DCE | 二氯乙烷 |
DMAP | 二甲氨基吡啶 |
DMF | 二甲基甲酰胺 |
DMSO | 二甲基亚砜 |
DIEA/DIPEA | N,N-二异丙基乙胺 |
DTT | 二硫苏糖醇 |
EDTA | 乙二胺四乙酸 |
equiv./eq. | 当量 |
Et | 乙基 |
h | 小时 |
HEPES | 4-(2-羟基乙基)-1-哌嗪乙磺酸 |
HPLC | 高压液相色谱法 |
LC/MS | 液相色谱法-质谱法 |
LiOH | 氢氧化锂 |
m | 多重峰 |
M | 分子离子 |
m/z | 质荷比 |
Me | 甲基 |
MeOH | 甲醇 |
min | 分钟 |
MS | 质谱法 |
N | 当量(浓度单位) |
NaOH | 氢氧化钠 |
NBS | N-溴代琥珀酰亚胺 |
NMO | 4-甲基吗啉N-氧化物 |
NMP | N-甲基-2-吡咯烷酮 |
NMR | 核磁共振 |
PG | 保护基团 |
psi | 磅/平方英寸 |
PyBOP | (苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐 |
q | 四重峰 |
Rf | 保留因子 |
RT/rt | 室温 |
Rt. | 保留时间 |
s | 单峰 |
T3P | 丙基磷酸环酐 |
TBAF | 四丁基氟化铵 |
Tert | 叔 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
THAB | 四己基溴化铵 |
THF | 四氢呋喃 |
UV | 紫外 |
VIS | 可见 |
NMR波谱
在配有自动化三宽带(ATB)探针的Varian UnityInova或Bruker 400MHz NMR分光计上获取NMR波谱。将ATB探针同时调至1H、19F和13C。对于典型的1H NMR波谱,脉冲角是45度,将8次扫描总和,谱宽是16ppm(-2ppm至14ppm)。在5.1秒采集时间内总共收集32768个复点,循环延迟设定为1秒。在25℃收集波谱。在进行傅里叶变换之前,通常用0.2Hz线增宽和对131072个点零填充来处理1H NMR波谱。
使用以下三个方法进行分析性LC/MS:
方法A:使用Discovery C18,5μm,3x30mm柱,流速400μL/分钟,进样环5μL,流动相(A)含0.1%甲酸的水,流动相(B)含0.1%甲酸的甲醇;保留时间以分钟计。方法详述:(I)使用Quaternary Pump G1311A(Agilent),备有UV/VIS二极管阵列检测器G1315B(Agilent)和Finnigan LCQ Duo MS检测器(ESI+模式),UV-检测在254和280nm,梯度:15-95%(B)3.2分钟线性梯度,(II)在95%(B)保持1.4分钟,(III)从95-15%(B)0.1分钟线性梯度,(IV)在15%(B)保持2.3分钟。
方法B:使用Waters Symmetry C18,3.5μm,4.6x75mm柱,流速1mL/分钟,进样环10μL,流动相(A)为含0.05%TFA的水,流动相(B)为含0.05%TFA的ACN;保留时间以分钟计。方法详述:(I)使用Binary Pump G1312A(Agilent),备有UV/Vis二极管阵列检测器G1315B(Agilent)和Agilent G1956B(SL)MS检测器(ESI+模式),UV-检测在254和280nm,梯度:20-85%(B)10分钟线性梯度,(II)在85%(B)保持1分钟,(III)从85-20%(B)0.2分钟线性梯度,(IV)在20%(B)保持3.8分钟。
方法C:梯度:4.2分钟/流速:2ml/分钟99∶01-0∶100水+0.1%(体积)TFA;乙腈+0.1%(体积)TFA;0.0至0.2分钟:99∶01;0.2至3.8分钟:99∶01→0∶100;3.8至4.2分钟:0∶100;柱:Chromolith Performance RP18e;长度100mm,直径3mm;波长:220nm。
分析型手性HPLC
使用来自Daicel Chemical Industries,Ltd.的ChiralPak AD-H柱(250X4.6mm)在Agilent 1100系列系统进行分析型手性HPLC。该方法使用5.0μL进样体积,流速1mL/分钟,使用100%甲醇在25℃运行15分钟,且UV-检测在254和280nm。
制备型HPLC
使用Waters Atlantis dC18OBD TM 10μM(30X250mm)柱或Waters Sunfire PrepC18OBD 10μM(30X250mm)柱进行制备型HPLC。所述柱在装备有进样环(10mL)和ISCO UA-6UV/Vis检测器的Waters Prep LC4000System以60mL/分钟的流速使用。流动相从含有(A)水和(B)HPLC-级乙腈的两个溶剂瓶中吸入。通常的制备使用线性梯度(例如,0-60%溶剂B经历60分钟)。
本发明还涉及根据下文所述流程和操作实施例制备化合物的方法。
通用合成流程
流程1A:将醇中间体A(WO12/69146)转化为相应的甲磺酸酯,再将甲磺酸酯与仲烷基胺反应,然后用盐酸进行Boc脱保护反应,得到所希望的胺盐酸盐中间体B。
流程1B:用仲烷基胺对中间体C(WO12/69146)进行亲核攻击,然后用盐酸进行Boc脱保护反应,得到所希望的胺盐酸盐中间体B。
流程2:用以对硝基苯磺酰基(nosyl)保护的伯胺对中间体C(WO12/69146)进行亲核攻击,然后用盐酸进行Boc脱保护反应,得到所希望的胺盐酸盐中间体D。
流程3:在NaOH水溶液存在下用高锰酸钾处理2-硝基-间二甲苯,得到2-硝基间苯二甲酸中间体。所述二酸在DMF中与亚硫酰氯回流,然后加入在THF中的氨水,得到2-硝基间苯二甲酰,用Pd/C氢化2-硝基间苯二甲酰,得到2-氨基间苯二甲酰胺中间体。在DMF中与在0.5M盐酸中的亚硝酸钠进行环化反应,得到所希望的4-氧代-3,4-二氢-苯并[d][1,2,3]三嗪-8-羧酰胺E。
流程4:3-氧代戊二酸二甲酯、三乙氧基甲烷和脲在甲苯中的混合物回流,得到4-氧代-1,4-二氢吡啶-3,5-二羧酸二甲酯,为沉淀物。该中间体再在磷酰氯中回流,得到4-氯吡啶中间体。将二酯和甲脒醋酸盐在1,4-二噁烷中的溶液用氢化钠处理,得到4-羟基吡啶并[4,3-d]嘧啶-8-羧酰胺F。
流程5:用高锰酸钾处理硝基吡啶,得到所希望的二酸,用碘乙烷处理二酸,得到二乙酯衍生物。采用钯为催化剂使硝基吡啶二酯进行氢化反应,得到氨基吡啶二酯,用甲酰胺环化所述二酯,得到产物G(主要产物)和H(次要产物),无需分离可直接使用。
流程6:用浓硫酸和亚硝酸钠处理氨基吡啶衍生物,得到吡啶酮衍生物,再用溴氧化磷处理吡啶酮衍生物,得到溴吡啶中间体。溴吡啶用氰化铜处理,得到腈衍生物,然后用硫酸处理腈,得到酰胺衍生物。用铁粉还原所得到的酰胺衍生物,生成所希望的氨基吡啶。氨基吡啶衍生物在过量原甲酸三乙酯存在下回流,得到所希望的吡啶并嘧啶酮中间体,用硫酸和重铬酸钾处理所述中间体,生成所希望的酸。
上述酸用在二甲基甲酰胺中的羰基二咪唑处理,再加入氨,则生成所希望的4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺G,或者加入甲醇,则生成所希望的4-羟基吡啶并[3,2-d]嘧啶-8-羧酸甲酯I。
流程7:50℃下氮杂-喹唑啉羧酰胺中间体J与胺中间体K在溶于DMSO或DMF或NMP中的DIEA和PyBop存在下反应,生成所希望的化合物L。
流程8:50℃下氮杂-喹唑啉羧酰胺中间体J与胺中间体D在溶于DMSO或DMF或NMP中的DIEA和PyBop存在下反应,生成对硝基苯磺酰基保护的中间体,在碳酸钾存在下用苯硫酚处理该中间体,生成所希望的化合物M。
流程9:50℃下氮杂-喹唑啉羧酰胺中间体J与胺中间体N在溶于DMSO或DMF或NMP中的DIEA和PyBop存在下反应,生成Boc保护的中间体,在甲醇存在下用HCl/二噁烷溶液处理该中间体,生成所希望的化合物O。
流程10:40℃下氮杂-喹唑啉羧酸甲酯中间体与胺中间体在溶于DMSO中的DIEA和PyBop存在下反应,生成对硝基苯磺酰基保护的中间体,在甲醇存在下用氨将该中间体转化为它的羧酰胺中间体。在碱存在下用巯基乙酸脱去对硝基苯磺酰基保护,生成所希望的化合物M。
流程11:氮杂-喹唑啉羧酰胺中间体J或氮杂-喹唑啉腈中间体P与三氧氯化磷反应,生成所希望的氯中间体。所述中间体与合适的胺反应,生成所希望的化合物Q(如果R’不是Nos)或者生成对硝基苯磺酰基保护的中间体(如果R’是Nos),在碱存在下用巯基乙酸处理该中间体,生成所希望的化合物M。
实施例1:中间体的合成
氨基苯基乙胺二盐酸盐(B)(流程1A)
将醇中间体A(3.17mmol)在DCM(5.00mL)中的溶液冷却至-78℃,用三乙胺(9.52mmol)和甲烷磺酰氯(4.76mmol)处理,然后搅拌30-60分钟,再用饱和碳酸氢钠溶液(10mL)淬灭反应。有机层用盐水萃取,硫酸镁干燥,过滤,浓缩,得到相应的甲磺酸酯,无需纯化可直接使用。甲磺酸酯用胺(若纯的胺,用2-5eq.;或者若胺在THF中的溶液,用1.5eq.)室温处理30-60分钟。得到所希望的2-苯基乙-1,2-二胺,其用乙酸乙酯稀释,再用饱和碳酸氢钠溶液萃取。有机层用盐水洗涤,硫酸镁干燥,过滤,浓缩。粗残留物经正相硅胶色谱法(20-50%乙酸乙酯在己烷中的溶液)提纯,获得纯的所希望的boc-保护的氨基苯基乙胺中间体,为白色固体,得率(55-78%)。
用4.0M HCI在1,4-二噁烷(1.1mmol,~5eq)中的溶液处理Boc-保护的氨基苯基乙胺中间体(0.22mmol)在无水DCM(2mL)中的悬液,内容物在室温搅拌。出现不溶物,沉淀出固体。3小时后,过滤收集固体,用二乙醚(10mL)洗涤,真空干燥2小时,获得产物B,为白色或乳白色固体(63-95%)。
氨基苯基乙胺二盐酸盐(B)(流程1B)
用仲胺(65.67mmol,1.25eq)处理环状砜中间体C(52.52mmol)在CH3CN(100mL)中的悬液,内容物在室温搅拌30-60分钟。沉淀出固体,过滤,用甲醇或丙酮(100mL)洗涤,真空干燥2小时,获得Boc-保护的氨基苯基乙胺中间体产物B,为白色固体(60-77%)。
用2.0M HCI在二乙醚(200mmol,~5eq)中的溶液处理Boc-保护的氨基苯基乙胺中间体(38.61mmol)在无水甲醇(50mL)中的悬液,内容物在室温搅拌。出现不溶物,沉淀出固体。3小时后,过滤收集固体,用二乙醚(100mL)洗涤,真空干燥2小时,获得产物B,为白色或乳白色固体(69-75%)。
氨基苯基乙胺二盐酸盐(D)(流程2)
将N-烷基-4-硝基苯磺酰胺(7.84mmol)加入至粉状氢氧化钾(15.68mmol)在CH3CN(30.00ml)中的悬液中,反应混合物搅拌15分钟。滴加入环状砜中间体C(7.47mmol)在MeCN(30.00ml)中的溶液,搅拌12小时。向反应混合物加入0.5N HCl(50mL),让溶液搅拌多15分钟。数分钟后出现沉淀物。过滤收集固体,用水(50mL)洗涤,真空干燥,获得Boc-保护的中间体,为褐色固体(50-60%)。
用2.0M HCI在二乙醚(4.6mmol,~5eq)中的溶液处理Boc-保护的中间体(0.77mmol)在无水甲醇(1mL)中的悬液,内容物在室温搅拌。出现不溶物,沉淀出固体。3小时后,反应混合物用二乙醚(10mL)稀释,过滤收集固体,用二乙醚(10mL)洗涤,真空干燥2小时,获得产物D,为褐色固体(65-75%)。
4-羟基苯并[d][1,2,3]三嗪-8-羧酰胺(E)(流程3)
2-硝基间苯二甲酸
2-硝基-间二甲苯(10.0g,0.066mol)和氢氧化钠(2.29g,0.072mol)在水(200mL)中的混合物加热至90℃,在3小时内分批加入高锰酸钾(41.0g,0.264mol)。反应混合物加热至90℃,保持20小时。通过硅藻土床滤出反应物,用热水(50mL)洗涤,6N HCl(pH>1)酸化。过滤收集沉淀出的固体,用水洗涤,抽吸干燥,得到标题化合物,为白色固体(72%得率)。LC-MS[210(M-H)],1H NMR(400MHz,DMSO-d6):δ8.18(d,J=7.80Hz,2H),7.80(t,J=7.80Hz,1H)。
2-硝基-间苯二甲酰胺
2-硝基-间苯二甲酸(10.0g,0.047mol)、亚硫酰氯(100mL)和DMF(0.1mL)的混合物加热至回流,在氮气气氛下回流16小时。减压蒸发反应混合物。残留物溶于THF(50mL)中,冷却至0℃,滴加入氨水(50mL)。反应混合物室温搅拌6小时,过滤收集沉淀出的固体,用水洗涤,抽吸干燥,得到标题化合物,为白色固体(61%得率)。LC-MS[208(M-H)],1H NMR(400MHz,DMSO-d6):δ8.28(brs,2H),7.77(brs,2H),7.74-7.67(m,3H)。
2-氨基间苯二甲酰胺
2-硝基-间苯二甲酰胺(6g,0.028mol)和Pd/C(0.6g)在DMF(100mL)中的混合物在室温和氢囊压力下进行加氢反应。反应混合物经硅藻土床过滤,用DMF洗涤,真空蒸发滤液,获得标题化合物,为褐色固体(得率78%)。LC-MS[178(M-H)],1H NMR(400MHz,DMSO-d6):δ7.97(s,2H),7.84(brs,2H),7.65(d,J=7.76Hz,2H),7.22(brs,2H),6.49(t,J=7.76Hz,1H)。
4-羟基苯并[d][1,2,3]三嗪-8-羧酰胺
0℃下将2-氨基-间苯二甲酰胺(4.0g,0.022mol)在DMF(40mL)中的溶液加入至亚硝酸钠(1.85g,0.0267mol)在0.5M HCl(120mL)中的溶液中。反应混合物室温过滤2小时,减压蒸发反应混合物。加入水使残留物变成浆液,过滤,抽吸干燥,获得标题化合物C,为白色固体(得率84%)。LC-MS[191(M+H)],1H NMR(400MHz,DMSO-d6)δ15.19(s,1H),8.48(s,1H),8.32-8.29(m,2H),7.94(dd,J=5.5,14.4Hz,2H)。
4-羟基吡啶并[4,3-d]嘧啶-8-羧酰胺(F)(流程4)
4-氧代-1,4-二氢吡啶-3,5-二羧酸二甲酯
3-氧代戊二酸二甲酯(12g,69mmol)、CH(OEt)3(15.1g,100mmol)和脲(6g,100mmol)在二甲苯(25mL)中的混合物加热至回流,保持3小时。混合物冷却至室温,滤出沉淀物,用二甲苯和DCM洗涤,获得标题化合物,为白色固体(得率82.3%)。
4-氯吡啶-3,5-二羧酸二甲酯
4-氧代-1,4-二氢吡啶-3,5-二羧酸二甲酯(3g,粗产物)和POCl3(10mL)的混合物在密封管内加热至140℃,保持15小时。混合物冷却至室温,倒入冰中,用醚萃取。有机层用盐水洗涤,Na2SO4干燥,过滤,浓缩,获得标题化合物,为固体(得率33.7%)。
4-羟基吡啶并[4,3-d]嘧啶-8-羧酸甲酯
向4-氯吡啶-3,5-二羧酸二甲酯(0.6g,2.6mmol)和甲脒醋酸盐(0.82g,7.8mmol)在二噁烷(20mL)中的混合物加入NaH(0.31g,7.8mmol)。得到的混合物回流48小时,冷却至室温。滤出沉淀物,用乙酸乙酯洗涤,获得标题化合物,为灰色固体(得率56.1%)。
4-羟基吡啶并[4,3-d]嘧啶-8-羧酰胺
4-羟基吡啶并[4,3-d]嘧啶-8-羧酸甲酯(47mg,0.1mmol)、NH4OH(3mL)和甲醇(10mL)的混合物在密封管内加热至回流,保持20小时。混合物浓缩,经制备型HPLC提纯,获得标题化合物,为白色固体(得率41.1%)。
4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)和4-羟基吡啶并[3,4-d]嘧啶-8-羧酰胺(H)(流程5)
3-硝基-吡啶-2,4-二羧酸
向氢氧化钠(515.24g;12881.94mmol)在水(15.00l;30.00V)中的溶液加入2,4-二甲基-3-硝基-吡啶(500.00g;3220.48mmol)。混合物在90℃搅拌,分批小量地加入高锰酸钾(5.25kg;32204.85mmol),混合物加热至回流,搅拌16小时。冷却至室温,通过硅藻土过滤混合物,用水(1L)洗涤。真空蒸发滤液至原体积的一半,将得到的溶液冷却至~5℃。滴加入HCl(浓的水溶液),调pH至~2。产物用乙酸乙酯(5x 3L)萃取。有机层合并,经Na2SO4干燥,真空蒸发,获得标题化合物,为黄色固体(得率12.4%)。LC-MS[167(M+H)],1H NMR(400MHz,DMSO-d6)14.2(bs,2H),9.0-8.99(d,2H),8.11-8.10(d,1H)。
3-硝基-吡啶-2,4-二羧酸二乙酯
向3-硝基-吡啶-2,4-二羧酸(110.00g;0.40mol)在DMF(1100.00ml;10.00V)中的溶液加入碳酸钾(170.02g;1.19mol)和碘乙烷(94.95ml;1.19mol)。反应物室温搅拌16小时。待反应完成后,滤出反应混合物,真空浓缩以移除滤液。残留物溶解在乙酸乙酯(1L)中,再次过滤和真空浓缩。残留物用冻水(1L)稀释,二乙醚(3x 1L)萃取。有机层合并,用水(2x300mL)洗涤,Na2SO4干燥,真空浓缩。残留物经柱硅胶色谱法(60-120目)提纯,洗脱液为5-10%乙酸乙酯:己烷,获得标题化合物,为褐色液体(得率51.6%)。LC-MS[269(M+H)],1HNMR(400MHz,CDCl3)8.94-8.93(d,1H),8.00-7.98(d,1H),4.48-4.38(m,4H),1.41-1.38(m,6H)。
3-氨基-吡啶-2,4-二羧酸二乙酯
向3-硝基-吡啶-2,4-二羧酸二乙醚(55.00g;0.19mol)的溶液加入Pa/C(10%w/w)(6.00g;0.01mol)。混合物在室温和5Kg氢气压力下搅拌4小时。待反应完成后,反应混合物经硅藻土过滤,真空浓缩滤液。残留物经柱色谱法(60-120目)提纯,洗脱液为15-20%乙酸乙酯:石油醚,获得标题化合物,为黄色固体(得率69.7%)。LC-MS[239(M+H)],1H NMR(400MHz,DMSO-d6),7.94-7.93(d,1H),7.84-7.83(d,1H),4.34-4.27(m,4H),1.33-1.29(m,6H)
4-羟基-吡啶并[3,2-d]嘧啶-8-羧酰胺(G)和4-羟基-吡啶并[3,4-d]嘧啶-8-羧酰胺(H)
3-氨基-吡啶-2,4-二羧酸二乙酯(30.00g;0.13mol)在甲酰胺(150.00ml;5.00V)中的溶液于140℃搅拌4天。反应混合物冷却至0℃。在0℃搅拌5小时后,滤出反应混合物,收集到的固体用水(20mL)洗涤。用异丙醇(20mL)使固体变成浆液,过滤,用异丙醇再次洗涤,抽吸干燥,获得标题化合物(G,主要产物)和(H,次要产物)的混合物,为灰色固体(得率50.1%)。LC-MS[189(M-H)],1H NMR(400MHz,DMSO-d6)12.42(bs,1H),9.33(s,1H),8.88-8.87(d,1H),8.33(s,1H),8.21-8.20(d,1H),8.13(s,1H)。
4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)(流程6)
4-甲基-3-硝基吡啶-2(1H)-酮
将2-氨基-4-甲基-3-硝基吡啶(120g,0.78mol)悬于水(1.6L)中,滴加入浓硫酸(120mL),澄清的黄色溶液在冰浴中冷却至0℃。通过长柄漏斗缓慢地加入溶解在水(250mL)中的亚硝酸钠(98g,1.42mol),加入的亚硝酸钠低于反应溶液的液体表面。反应混合物室温搅拌2小时,沸腾至看不到有褐色气体逸出。冷却反应溶液,过滤,干燥,获得标题化合物(得率91.6%)。
2-溴-4-甲基-3-硝基吡啶
4-甲基-3-硝基吡啶-2(1H)-酮(110g,0.71mol)悬于二氯乙烷(1L)中。室温下向上述悬液滴加入溴氧化磷(317g,1.1mol)在二氯乙烷(1L)中的溶液。反应混合物回流12小时。混合物冷却至室温,倒入冰水中,用碳酸钾中和。分离出有机层,用水和盐水洗涤,硫酸钠干燥。蒸发溶剂,得到标题化合物(得率71.8%)。
4-甲基-3-硝基甲基吡啶腈
溴吡啶(110g,0.51mol)和新制备的氰化铜(50g,0.56mol)在DMF(1L)中加热至100℃,保持13小时。反应混合物冷却至室温,倒入乙酸乙酯/水的混合物(1.5L:3L)中。将得到的三相混合物从无机固体材料滤出。分离出有机相,用水洗涤,硫酸钠干燥。蒸发溶剂,获得标题化合物(得率63.7%)。
4-甲基-3-硝基吡啶酰胺
将腈衍生物(106g,0.65mol)小心地溶解在90%硫酸(350mL)中。反应混合物在70℃加热3小时。再将反应混合物冷却至室温,倒入碎冰中。滤出沉淀的酰胺,减压干燥(得率59.5%)。
3-氨基-4-甲基吡啶酰胺
向配有机械搅拌棒的三颈圆底烧瓶(4L)加入溶解在i-PrOH(2L)中的硝基衍生物(70g,0.39mol)。加入NH4Cl(7g)、HCl(7mL)、水(7mL)。反应混合物加热至回流。分批小量地加入铁粉(156g,2.8mol)。待起始材料完全反应完成后,分批小量地加入碳酸钠(106g,2.8mol)。滤出热的反应混合物;用热乙醇洗涤不溶材料多次。蒸发溶剂,获得胺产物(得率61.5%)。
8-甲基吡啶并[3,2-d]嘧啶-4(3H)-酮
胺衍生物(37g,0.24mol)在过量原甲酸三乙酯(500mL)存在下回流24小时。收集沉淀物,用MTBE洗涤,获得标题化合物(得率90.5%)。
4-氧代-3,4-二氢吡啶并[3,2-d]嘧啶-8-羧酸
向配有机械搅拌棒的二颈圆底烧瓶(2L)加入98%浓硫酸(350mL,d=1.98)。向混合物小心地加入嘧啶酮(35g,217mmol)。向反应混合物分批加入重铬酸钾(95.8g,0.33mol),保持温度在20–30℃之间。反应混合物室温搅拌过夜。向反应混合物加入碳酸钾,调pH~1。滤出形成的沉淀物,用水洗涤,减压干燥,获得标题化合物(得率72.4%)。
4-羟基-吡啶并[3,2-d]嘧啶-8-羧酰胺
将酸中间体(8.3g,43mmol)溶解在DMF(200mL)中,加入CDI(8.8g,54mmol)。反应混合物加热至70℃,观察到气体逸出。待看不到有气体逸出后,在同一温度下加热反应混合物1小时,得到澄清溶液。加入25%氨水(30ml,10eq.),反应混合物在70℃加热过夜。反应混合物冷却至室温,减压蒸发溶剂。残留物用水稀释,过滤,再用水洗涤,减压干燥,获得标题化合物(得率81.9%)。
4-羟基吡啶并[3,4-d]嘧啶-8-羧酸甲酯(I)(流程6)
4-氧代-3,4-二氢吡啶并[3,2-d]嘧啶-8-羧酸(39.0g,0.20mol)溶解在无水NMP(700mL)中,加入CDI(41.3g,0.26mol,10eq.)。反应混合物加热至70℃,观察到气体逸出。待看不到有气体逸出后,在同一温度下加热反应混合物1小时,得到澄清溶液。加入甲醇(65g,2mol),反应混合物在70℃加热过夜。反应混合物冷却至室温,沉淀出有机材料。过滤,用甲醇洗涤,减压干燥,获得标题化合物(I)(得率75.0%)。
4-取代-氮杂-喹唑啉-8-羧酰胺(L)(流程7)
在氩气气氛下将氮杂-喹唑啉羧酰胺J(0.21mmol)、胺中间体K(0.21mmol)和DIEA(0.86mmol)的混合物悬于溶剂(DMF或NMP或DMSO)(2.00mL)中。反应混合物室温搅拌5分钟,然后加入PyBOP(0.59mmol)。反应混合物室温搅拌12小时。反应混合物用水(10mL)稀释,乙酸乙酯(3x 10mL)萃取。有机层合并,硫酸钠干燥,浓缩。残留物经反相HPLC或Biotage色谱法提纯,获得所希望的产物L,为乳白色固体(11-40%)。
4-取代-氮杂-喹唑啉-8-羧酰胺(M)(流程8)
在氩气气氛下将对硝基苯磺酰基保护的胺D(0.34mmol)、氮杂-喹唑啉羧酰胺J(0.44mmol)和DIEA(0.68mmol)悬于DMSO(3.00mL)中。反应混合物40℃搅拌12小时。滤出反应混合物,经反相HPLC或Biotage色谱法提纯,获得所希望的对硝基苯磺酰基保护的中间体,为乳白色固体(40-92%)。
向对硝基苯磺酰基保护的中间体(0.38mmol)在DMF(3.00ml)中的溶液加入碳酸钾(1.13mmol),悬液搅拌10分钟。注射加入苯硫酚(1.51mmol),室温下强烈地搅拌溶液过夜。滤出反应混合物,经反相HPLC或Biotage色谱法提纯,获得所希望产物M,为白色固体(65-85%)。
4-取代-氮杂-喹唑啉-8-羧酰胺(O)(流程9)
在氩气气氛下将Boc保护的胺N(0.34mmol)、氮杂-喹唑啉羧酰胺J(0.53mmol)、DIEA(1.58mmol)和PyBOP(0.79mmol)悬于DMSO(2.00mL)中。反应混合物50℃搅拌18小时。反应混合物分隔在乙酸乙酯(25mL)和饱和碳酸氢钠溶液(5mL)之间,分离两相。有机相用水(5mL)洗4次,再用盐水洗涤。有机层经硫酸钠干燥,过滤,浓缩。反应混合物经硅胶Biotage色谱法(乙酸乙酯/己烷)提纯,获得所希望的Boc保护的中间体,为乳白色固体(26-48%)。
室温下向Boc保护的中间体(0.12mmol)在甲醇(1.5ml)中的溶液加入4N HCl在1,4-二噁烷(0.50mL)中的溶液,悬液搅拌1小时。反应混合物过滤,经反相HPLC提纯,得到产物O,为白色固体(44-72%)。
4-取代-氮杂-喹唑啉-8-羧酰胺(M)(流程10)
在氩气气氛下将氮杂-喹唑啉羧酸甲酯(2.4mmol)、DIEA(4.8mmol)和PyBOP(2.9mmol)的混合物悬于DMSO(10mL)中。反应混合物室温搅拌10分钟,然后加入对硝基苯磺酰基保护的胺(2.4mmol)。反应物在40℃搅拌过夜。冷却至室温后,反应混合物用乙酸乙酯稀释,饱和碳酸氢钠溶液洗涤。分离出有机相,用1M HCl(1x)洗涤,再用水(4x)和盐水(1x)洗涤。有机相经Na2SO4干燥,过滤,真空浓缩,得到粗产物,该粗产物经Biotage色谱法提纯,获得所希望的甲酯中间体,为浅黄色泡沫(50-65%)。
甲酯中间体(1.5mmol)在7N氨中的溶液与甲醇(12mL)的反应混合物室温搅拌过夜。浓缩反应混合物,得到对硝基苯磺酰基保护的酰胺中间体(80-85%)。
向对硝基苯磺酰基保护的酰胺中间体(0.6mmol)在乙腈(2mL)中的溶液加入DBU(1.8mmol)和巯基乙酸(0.9mmol)。反应混合物室温搅拌过夜。反应物浓缩,溶解在DCM中,用饱和碳酸氢钠溶液洗涤,再用盐水洗涤。有机层经硫酸钠干燥,过滤,浓缩,得到粗产物。粗产物在二氯甲烷中研磨,分离得到所希望的酰胺M,获得乳白色固体(70-85%)。
4-取代-氮杂-喹唑啉-8-羧酰胺(Q)(流程11)
氮杂-喹唑啉羧酰胺J(1.92mmol)在磷酰氯(215mmol)存在下回流12-18小时。完成后,旋转蒸发真空浓缩反应混合物。残留物溶解在冷乙酸乙酯中,用冰冻的饱和碳酸氢钠溶液洗涤。有机层用盐水洗涤,硫酸钠干燥,过滤,浓缩,获得所希望的双环氯化物中间体,为黄色固体(34-94%)。
在配有磁搅拌棒的干净的干圆底烧瓶中将胺(8.43mmol)悬于乙腈(85mL)。向上述悬液加入Hunig′s碱(50mmol)和硫酸钠(28mmol)。获得的悬液搅拌5分钟,加入双环氯化物中间体(8.43mmol)。反应混合物搅拌并加热至40℃,保持加热12-18小时。完成后,旋转蒸发真空浓缩反应混合物。残留物经快速硅胶色谱法提纯,洗脱液为20-50%乙酸乙酯的己烷溶液,获得所希望的腈中间体,为浅黄色固体(24-60%)。
室温下向腈中间体(1.37mmol)和氢氧化钠(5.46mmol)在异丙醇(5.00ml)和最小量的DMSO(0.5mL)中的混合物加入过氧化氢(8.2mmol)。混合物搅拌至反应完成。用水(20mL)稀释反应混合物,分离出所希望的酰胺化合物Q,然后过滤出固体(75-95%)。
4-取代-氮杂-喹唑啉-8-羧酰胺(M)(流程11)
向对硝基苯磺酰基保护的酰胺中间体(5.74mmol)在乙腈(15mL)中的溶液加入DBU(17.2mmol)和巯基乙酸(8.61mmol)。反应混合物室温搅拌。完成后,浓缩反应混合物,溶解在二氯甲烷中,用饱和碳酸氢钠溶液洗涤,再用盐水溶液洗涤。有机层经硫酸钠干燥,过滤,浓缩,获得粗产物。用二氯甲烷研磨粗产物,再分离出所希望的酰胺M,为乳白色固体(57-95%)。
实施例2:本发明化合物的合成
4-(3-三氟甲基-苄基氨基)-苯并[d][1,2,3]三嗪-8-羧酰胺(1)
依据通用合成流程7的方法,使3-三氟甲基-苄胺与4-羟基苯并[d][1,2,3]三嗪-8-羧酰胺反应,制备标题化合物1。LC-MS[348(M+1)],1HNMR(400MHz,DMSO-d6):δ9.36-9.33(m,2H),8.55-8.49(m,2H),8.04(s,1H),8.02-7.98(m,1H),7.80(s,1H),7.72(d,1H),7.64(d,1H),7.59-7.56(m,1H),5.00(d,2H)。
4-((3,4-二氯苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(2)
依据通用合成流程7的方法,使(3,4-二氯苯基)甲胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物2。LC-MS[350(M+1)],1H NMR(400MHz,DMSO-d6):δ9.37(s,1H),9.31(t,1H),8.54(d,1H),8.49(d,1H),8.05(s,1H),8.00(t,1H),7.70(s,1H),7.60(d,1H),7.40(d,1H),4.90(d,1H)。
4-((吡啶-3-基甲基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(3)
依据通用合成流程7的方法,使吡啶-3-基甲胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物3。LC-MS[281(M+1)],1H NMR(400MHz,DMSO-d):δ9.38-9.32(m,2H),8.66(s,1H),8.54(d,1H),8.50-8.48(m,2H),8.05(s,1H),7.99(t,1H),7.82(d,1H),7.38-7.35(m,1H),4.93(s,2H)。
4-((4-氯-3-(三氟甲基)苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(4)
依据通用合成流程7的方法,使(4-氯-3-(三氟甲基)苯基)甲胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物4。LC-MS[382(M+1)],1H NMR(400MHz,DMSO-d):δ9.38-9.32(m,2H),8.54(d,1H),8.48(d,1H),8.05(s,1H),8.02-7.98(m,1H),7.95(s,1H),7.73-7.68(m,2H),4.96(d,2H)。
4-((吡啶-2-基甲基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(5)
依据通用合成流程7的方法,使吡啶-2-基甲胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物5。LC-MS[281(M+1)],1H NMR(400MHz,DMSO-d):δ9.40(s,2H),8.56-8.51(m,3H),8.04(s,1H),8.00(t,1H),7.76-7.72(m,1H),7.40(d,1H),7.29-7.26(m,1H),4.99(d,2H)。
4-(苄基氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(6)
依据通用合成流程7的方法,使苄胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物6。LC-MS[280(M+1)],1H NMR(400MHz,DMSO-d):δ9.42(s,1H),9.31(t,1H),8.53(t,1H),8.04(s,1H),7.98(t,1H),7.41(d,2H),7.34(t,2H),7.28-7.24(m,1H),4.92(d,2H)。
4-(((5-(三氟甲基)吡啶-2-基)甲基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(7)
依据通用合成流程7的方法,使(5-(三氟甲基)-吡啶-2-基)甲胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物7。LC-MS[349(M+1)],1H NMR(400MHz,DMSO-d):δ9.50(t,1H),9.35(s,1H),8.93(s,1H),8.55(d,2H),8.16(dd,1H),8.05-8.01(m,2H),7.65(d,1H),5.07(d,2H)。
4-((4-(三氟甲基)苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(8)
依据通用合成流程7的方法,使(4-(三氟甲基)苯基)甲胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物8。LC-MS[348(M+1)],1H NMR(400MHz,DMSO-d):δ9.40-9.37(m,2H),8.56-8.51(m,2H),8.05(s,1H),8.01(t,1H),7.70(d,2H),7.62(d,2H),4.99(d,2H)。
4-((3-氟苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(9)
依据通用合成流程7的方法,使(3-氟苯基)甲胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物9。LC-MS[298(M+1)],1H NMR(400MHz,DMSO-d6):9.39(s,1H),9.32(s,1H),8.55-8.50(m,2H),8.05(s,1H),7.99(t,1H),7.41-7.35(m,1H),7.26-7.23(m,2H),7.11-7.09(m,1H),4.93(d,2H)。
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-甲氧基苯基)乙基)氨基)-苯并[d]
[1,2,3]三嗪-8-羧酰胺(10)
依据通用合成流程7的方法,使(S)-2-(氮杂环丁烷-1-基)-1-(4-氯-3-甲氧基苯基)乙胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物10。LC-MS[413(M+1)],1H NMR(400MHz,DMSO-d6):δ10.01(s,1H),9.29(s,1H),9.08(d,1H),8.58(d,2H),8.08(t,2H),7.44(d,2H),7.15(dd,1H),6.05-6.00(m,1H),4.44-4.41(m,1H),4.26-4.22(m,1H),4.21-4.05(m,2H),3.89(s,3H),3.80-3.74(m,3H),2.49-2.40(m,2H)。
(S)-4-((1-(4-氯-3-甲氧基苯基)-2-(二甲基氨基)乙基)氨基)-苯并[d][1,2,3]
三嗪-8-羧酰胺(11)
依据通用合成流程7的方法,使(S)-1-(4-氯-3-甲氧基苯基)-N2,N2-二甲基乙烷-1,2-二胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物11。LC-MS[401(M+1)],1H NMR(400MHz,DMSO-d6):δ9.51(s,1H),9.27(s,1H),9.09(d,1H),8.58(dd,2H),8.08(t,2H),7.44(d,2H),7.18(dd,1H),6.26(t,1H),3.89(s,3H),3.83-3.76(m,1H),3.62-3.57(m,1H),2.92(d,6H)。
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氟-3-(三氟甲基)苯基)乙基)氨基)苯并 [d][1,2,3]三嗪-8-羧酰胺(12)
依据通用合成流程7的方法,使4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺与(S)-2-(氮杂环丁烷-1-基)-1-(4-氟-3-(三氟甲基)苯基)乙胺反应,制备标题化合物12,为白色固体。LC-MS[435(M+1)].
(S)-4-((1-(4-氯-3-(三氟甲基)苯基)-2-(二甲基氨基)乙基)氨基)苯并-[d][1, 2,3]三嗪-8-羧酰胺(13)
依据通用合成流程7的方法,使(S)-1-(4-氯-3-(三氟甲基)苯基)-N2,N2-二甲基乙烷-1,2-二胺与4-羟基苯并[d][1,2,3]三嗪-8-羧酰胺反应,制备标题化合物13。LC-MS[439(M+1)],1H NMR(400MHz,DMSO-d6):δ9.61(brs,1H),9.23(s,1H),9.17(s,1H),8.58(s,2H),8.19(s,1H),8.08(d,J=8.0Hz,2H),7.92(s,1H),7.78(d,J=7.2Hz,1H),6.34(s,1H),3.83-3.63(m,2H),2.91(s,6H)。
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙基)氨基)苯并
[d][1,2,3]三嗪-8-羧酰胺(14)
依据通用合成流程7的方法,使(S)-2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙-1-胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物14。LC-MS[451(M+1)],1H NMR(400MHz,DMSO-d6):δ9.30(s,1H),8.87(d,1H),8.63(d,1H),8.54(d,1H),8.05-8.01(m,3H),7.81(d,,1H),7.70(d,1H),5.59(d,1H),3.21-3.14(m,4H),3.02(t,1H),2.99-2.78(m,1H),1.92(t,2H)。
(S)-4-((1-(3,4-二氯苯基)-2-(二甲基氨基)乙基)氨基)苯并[d][1,2,3]三嗪-
8-羧酰胺(15)
依据通用合成流程7的方法,使(S)-1-(3,4-二氯苯基)-N2,N2-二甲基乙烷-1,2-二胺与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物15。LC-MS[407(M+1)],1H NMR(400MHz,DMSO-d6):δ9.63(s,1H),9.24(s,1H),9.12(d,1H),8.59-8.56(m,2H),8.10-8.06(m,2H),7.95(d,1H),7.69(d,1H),7.60(dd,1H),6.25(t,1H),3.80(t,1H),3.61-3.59(m,1H),2.91(d,6H)。
(S)-4-((2-(氮杂环丁烷-1-基)-1-(3,4-二氯苯基)乙基)氨基)苯并[d][1,2,3]
三嗪-8-羧酰胺(16)
依据通用合成流程7的方法,使(S)-2-(氮杂环丁烷-1-基)-1-(3,4-二氯苯基)乙胺与4-羟基苯并[d][1,2,3]三嗪-8-羧酰胺反应,制备标题化合物16。LC-MS[417(M+1)]。
(S)-4-((1-(4-氯-3-氰基苯基)-2-(二甲基氨基)乙基)氨基)-苯并[d][1,2,3]三
嗪-8-羧酰胺(17)
依据通用合成流程7的方法,使(S)-5-(1-氨基-2-(二甲基氨基)乙基)-2-氯苯甲腈与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物17。LC-MS[397(M+1)],1H NMR(400MHz,DMSO-d6):δ9.31(s,1H),8.81(d,1H),8.63(d,1H),8.55(d,1H),8.15(d,1H),8.05-8.01(m,2H),7.88(dd,1H),7.72(d,1H),5.78(q,1H),2.95-2.89(m,1H),2.62-2.58(m,1H),2.24(s,6H)。
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-氰基苯基)乙基)氨基)苯并[d][1,2,
3]三嗪-8-羧酰胺(18)
依据通用合成流程7的方法,使(S)-5-(1-氨基-2-(氮杂环丁烷-1-基)乙基)-2-氯苯甲腈与4-羟基苯并[d][1,2,3]-三嗪-8-羧酰胺反应,制备标题化合物18。LC-MS[408(M+1)],1H NMR(400MHz,DMSO-d6):δ9.31(s,1H),8.82(d,1H),8.63(d,1H),8.55(d,1H),8.12(d,1H),8.03(t,2H),7.85(dd,1H),7.72(d,1H),5.54(d,1H),3.21-3.12(m,4H),3.02-2.97(m,1H),2.83-2.79(m,1H)。
(R)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙基)氨基)吡啶并 [4,3-d]嘧啶-8-羧酰胺(19)
依据通用合成流程7的方法,使(R)-2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙胺与4-羟基吡啶并[4,3-d]嘧啶-8-羧酰胺反应,制备标题化合物19,为乳白色固体。LC-MS[451(M+1)],1H NMR(400MHz,氯form-d)δ10.43(s,1H),9.75(s,1H),9.59(s,1H),8.62(s,1H),7.98(s,1H),7.69(s,1H),7.48(d,2H),6.12(s,1H),5.18(d,1H),3.25(dq,4H),3.05–2.89(m,2H),2.14(p,2H)。
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙基)氨基)吡啶并 [4,3-d]嘧啶-8-羧酰胺(20)
依据通用合成流程7的方法,使(S)-2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙胺与4-羟基吡啶并[4,3-d]嘧啶-8-羧酰胺反应,制备标题化合物20。LC-MS[451(M+1)],1H NMR(400MHz,氯form-d)δ10.43(s,1H),9.75(s,1H),9.59(s,1H),8.62(s,1H),7.98(s,1H),7.69(s,1H),7.48(d,2H),6.12(s,1H),5.18(d,1H),3.25(dq,4H),3.05–2.89(m,2H),2.14(p,2H)。
4-((4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(21)
依据通用合成流程9的方法,使4-羟基-苯并[d][1,2,3]三嗪-8-羧酸酰胺与3-氨基-4-(3-(三氟甲基)苯基)哌啶-1-羧酸叔丁酯反应,制备标题化合物21。LC-MS[417(M+H)],1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.98(d,1H),8.84(t,1H),8.54(d,1H),8.50(d,1H),8.30(d,1H),8.04–7.89(m,2H),7.67(s,1H),7.59(t,1H),7.45(d,2H),5.42–5.26(m,1H),3.64(d,1H),3.49(d,1H),3.35(td,1H),3.23–2.90(m,2H),2.52–2.00(m,2H)。
4-((4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺(22)
依据通用合成流程9的方法,使4-羟基-苯并[d][1,2,3]三嗪-8-羧酸酰胺与3-氨基-4-(4-(三氟甲基)苯基)哌啶-1-羧酸叔丁酯反应,制备标题化合物22。LC-MS[417(M+H)],1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),9.04–8.92(m,1H),8.61–8.43(m,3H),8.11–7.92(m,2H),7.72(d,1H),7.64–7.46(m,5H),5.58–5.44(m,1H),3.71–3.44(m,4H),3.30–3.09(m,1H),2.81–2.60(m,1H),2.08(d,1H)。
4-[4-(3-氯-4-氟-苯基)-哌啶-3-基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺(23)
依据通用合成流程9的方法,使4-羟基-吡啶并[3,2-d]嘧啶-8-羧酸酰胺与3-氨基-4-(3-氯-4-氟-苯基)哌啶-1-羧酸叔丁酯反应,制备标题化合物23。LC-MS[401(M+H)].
4-((4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)吡啶并[3,2-d]嘧啶-8-羧酰胺(24)
依据通用合成流程9的方法,使4-羟基-吡啶并[3,2-d]嘧啶-8-羧酸酰胺与3-氨基-4-(3-(三氟甲基)苯基)哌啶-1-羧酸叔丁酯反应,制备标题化合物24。LC-MS[417(M+H)],1H NMR(400MHz,DMSO-d6)δ9.78(d,1H),9.06(d,1H),9.03–8.95(m,1H),8.90(d,1H),8.88–8.73(m,1H),8.50(s,1H),8.32(d,1H),8.16(d,1H),7.62(s,1H),7.56(q,1H),7.43(d,2H),5.22–5.02(m,1H),3.60–3.38(m,3H),3.14(q,1H),2.99(q,1H),2.54(d,1H),2.08(dt,2H)。
4-((4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)吡啶并[3,2-d]嘧啶-8-羧酰胺(25)
依据通用合成流程9的方法,使4-羟基-吡啶并[3,2-d]嘧啶-8-羧酸酰胺与3-氨基-4-(4-(三氟甲基)苯基)哌啶-1-羧酸叔丁酯反应,制备标题化合物25。LC-MS[417(M+H)],1H NMR(400MHz,DMSO-d6)δ9.77(d,1H),8.99(d,1H),8.93–8.82(m,1H),8.82–8.70(m,1H),8.65(d,1H),8.36(d,2H),8.16(d,1H),7.48(t,4H),5.37–5.21(m,1H),3.75–3.42(m,1H),3.26–3.06(m,1H),2.02(d,1H)。
4-[(S)-1-(3-氟-4-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(26)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氟-4-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物26,为白色固体。LC/MS[409(M+H)];1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.20(s,1H),9.01(dd,J=4.7,1.7Hz,1H),8.54(d,J=1.7Hz,1H),8.45–8.34(m,1H),8.25–8.10(m,1H),7.72(t,J=7.8Hz,1H),7.61(d,J=12.1Hz,1H),7.49(d,J=8.1Hz,1H),5.53(t,J=6.5Hz,1H),3.21–3.08(m,1H),3.05–2.88(m,1H),2.30(s,3H),2.01(s,1H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(4-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(27)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(4-三氟甲基-苯基)-乙胺二盐酸盐反应,制备标题化合物27,为白色固体。LC/MS[417(M+H)];1H NMR(400MHz,DMSO-d6)δ9.92(d,J=3.4Hz,1H),9.11(d,J=7.9Hz,1H),9.01(dd,J=4.5,1.0Hz,1H),8.53(s,1H),8.38(dd,J=4.5,1.0Hz,1H),8.16(d,J=3.4Hz,1H),7.83–7.50(m,3H),5.36(q,J=7.2Hz,1H),3.21–2.99(m,4H),2.84(dd,J=12.0,5.6Hz,1H),1.92(p,J=6.9Hz,2H)。
4-[(S)-1-(3-溴-4-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧 酸酰胺(28)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-溴-4-氟-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物28,为褐色固体。LC/MS[419(M+H)];1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.40(d,1H),9.02(dd,1.9Hz,1H),8.60(d,1H),8.40(dd,1H),8.19(s,1H),8.04–7.76(m,1H),7.55(ddd,4.7,2.1Hz,1H),7.36(td,1H),5.88–5.57(m,1H),3.48(t,1H),3.21(dd,1H),2.54(d,1H),2.50(s,3H)。
4-[(S)-2-乙基氨基-1-(3-氟-4-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(29)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氟-4-三氟甲基-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物29,为浅黄色固体。LC/MS[423(M+H)];1H NMR(400MHz,DMSO-d6)δ9.93(d,J=3.7Hz,1H),9.25(d,J=7.8Hz,1H),9.01(d,J=4.5Hz,1H),8.54(s,1H),8.39(d,J=4.5Hz,1H),8.19(d,J=3.8Hz,1H),7.73(t,J=7.9Hz,1H),7.62(d,J=12.0Hz,1H),7.49(d,J=8.1Hz,1H),5.51(q,J=4.9Hz,1H),3.20(dd,J=12.5,8.1Hz,1H),3.03(dd,J=12.4,5.2Hz,1H),2.70–2.53(m,2H),0.99(t,J=7.1Hz,3H)。
4-[(S)-1-(3-溴-4-氟-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧 酸酰胺(30)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-溴-4-氟-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物30,为白色固体。LC/MS[434(M+H)];1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.36(s,1H),9.02(d,J=4.5Hz,1H),8.60(s,1H),8.40(d,J=4.4Hz,1H),8.18(s,1H),7.87(d,J=4.9Hz,1H),7.53(d,J=5.5Hz,1H),7.35(t,J=8.7Hz,1H),5.78–5.51(m,1H),3.55–3.36(m,1H),3.23–3.10(m,1H),2.93–2.69(m,2H),1.08(t,J=7.0Hz,3H)。
4-[(S)-1-(2,5-二氟-4-甲氧基-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(31)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(2,5-二氟-4-甲氧基-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物31,为浅黄色固体。LC/MS[403(M+H)];1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.03(d,J=26.0Hz,1H),8.98(s,1H),8.56(s,1H),8.37(d,J=4.5Hz,1H),8.16(s,1H),7.40(dd,J=12.1,7.0Hz,1H),7.09(dd,J=11.5,7.3Hz,1H),5.69(s,1H),3.82(s,3H),3.13(dd,J=12.3,8.5Hz,1H),2.91(dd,J=12.4,5.2Hz,1H),2.63–2.53(m,2H),1.85(s,1H),0.97(t,J=7.1Hz,3H)。
4-[(S)-1-(2,5-二氟-4-甲氧基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(32)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(2,5-二氟-4-甲氧基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物32,为白色固体。LC/MS[389(M+H)];1H NMR(400MHz,DMSO-d6)δ10.03–9.86(m,1H),9.04(s,1H),8.98(d,J=4.5Hz,1H),8.56(s,1H),8.37(d,J=4.5Hz,1H),8.24–8.07(m,1H),7.42(dd,J=12.1,7.0Hz,1H),7.09(dd,J=11.5,7.2Hz,1H),5.72(s,1H),3.82(s,3H),3.11(dd,J=12.3,8.5Hz,1H),2.85(dd,J=12.4,5.3Hz,1H),2.54(s,1H),2.30(s,3H)。
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(33)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氯-3-三氟甲基-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物33,为褐色固体。LC/MS[439(M+H)];1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.27(s,1H),9.00(d,J=4.5Hz,1H),8.54(s,1H),8.38(d,J=4.5Hz,1H),8.16(s,1H),8.00(d,J=1.8Hz,1H),7.76(dd,J=8.3,1.9Hz,1H),7.66(d,J=8.3Hz,1H),5.51(s,1H),3.17(dd,J=12.4,8.0Hz,1H),3.00(dd,J=12.4,5.6Hz,1H),2.60–2.55(m,2H),2.54(s,1H),0.97(t,J=7.1Hz,3H)。
4-[(S)-2-乙基氨基-1-(3-氟-5-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(34)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氟-5-三氟甲基-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物34,为浅黄色固体。LC/MS[423(M+H)];1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.24(s,1H),9.01(d,J=4.5Hz,1H),8.55(s,1H),8.38(d,J=4.4Hz,1H),8.16(s,1H),7.74(s,1H),7.66(d,J=9.8Hz,1H),7.53(d,J=8.9Hz,1H),5.73–5.28(m,1H),3.28(s,1H),3.23–3.10(m,1H),3.06–2.93(m,1H),2.56(d,J=7.1Hz,2H),0.97(t,J=7.2Hz,3H)。
4-[(S)-1-(3-氟-5-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(35)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氟-5-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物35,为白色固体。LC/MS[409(M+H)];1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.25(s,1H),9.01(d,J=4.5Hz,1H),8.55(s,1H),8.38(d,J=4.5Hz,1H),8.16(s,1H),7.74(s,1H),7.67(d,J=9.3Hz,1H),7.53(d,J=8.7Hz,1H),5.57(s,1H),3.15(dd,J=12.3,8.3Hz,1H),2.95(dd,J=12.3,5.5Hz,1H),2.30(s,3H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氯-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(36)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(4-氯-苯基)-乙胺二盐酸盐反应,制备标题化合物36,为乳白色固体。LC/MS[383(M+H)];1H NMR(500MHz,DMSO-d6)δ9.94(s,1H),9.27–8.84(m,2H),8.53(s,1H),8.37(d,J=4.4Hz,1H),8.17(s,1H),7.49(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),5.37–4.98(m,2H),3.16–2.94(m,3H),2.78(dd,J=11.9,5.3Hz,1H),2.07–1.65(m,2H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(4-异丙基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(37)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(4-异丙基-苯基)-乙胺二盐酸盐反应,制备标题化合物37,为乳白色固体。LC/MS[391(M+H)];1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),9.38–8.87(m,2H),8.53(s,1H),8.37(d,J=4.4Hz,1H),8.17(s,1H),7.37(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),5.60–4.97(m,1H),3.16–2.99(m,5H),2.89–2.77(m,1H),2.74(dd,J=11.9,4.9Hz,1H),2.02–1.72(m,2H),1.16(d,J=6.8Hz,6H)。
4-[(S)-2-甲基氨基-1-(4-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(38)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物38,为白色固体。LC/MS[391(M+H)];1H NMR(500MHz,DMSO-d6)δ9.93(s,1H),9.21(s,1H),9.00(d,J=4.4Hz,1H),8.52(s,1H),8.38(d,J=4.4Hz,1H),8.17(s,1H),7.68(s,4H),5.53(s,1H),3.20–3.07(m,1H),2.94(dd,J=12.2,4.9Hz,1H),2.30(s,3H)。
4-[(S)-1-(4-异丙基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧 酸酰胺(39)
依据通用合成流程8的方法,使4-羟基-吡啶并[3,2-d]嘧啶-8-羧酰胺(G)和4-羟基-吡啶并[3,4-d]嘧啶-8-羧酰胺(H)的混合物与N-[(S)-2-氨基-2-(4-异丙基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备化合物39。分离出的标题化合物为主要产物(白色固体)。LC/MS[365(M+H)];1H NMR(500MHz,DMSO-d6)δ9.92(s,1H),9.47(d,J=8.6Hz,1H),9.03(d,J=4.3Hz,1H),8.63(s,1H),8.41(d,J=4.3Hz,1H),8.22(s,1H),7.43(d,J=8.1Hz,2H),7.25(d,J=8.1Hz,2H),5.92–5.76(m,1H),3.89–3.65(m,1H),3.39(d,J=12.6Hz,1H),2.94–2.81(m,1H),2.61(s,3H),1.16(d,J=6.8Hz,6H)。
4-[(S)-1-(4-异丙基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,4-d]嘧啶-8-羧 酸酰胺(40)
依据通用合成流程8的方法,使4-羟基-吡啶并[3,2-d]嘧啶-8-羧酰胺(G)和4-羟基-吡啶并[3,4-d]嘧啶-8-羧酰胺(H)的混合物与N-[(S)-2-氨基-2-(4-异丙基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备化合物40。分离出的标题化合物为次要产物(白色固体)。LC/MS[365(M+H)];1H NMR(500MHz,DMSO-d6)δ9.14(s,2H),8.82–8.58(m,2H),8.40(s,1H),7.82(s,1H),7.42(d,J=7.8Hz,2H),7.26(d,J=7.9Hz,2H),6.52(s,1H),5.89(s,1H),3.68–3.54(m,1H),3.51–3.43(m,1H),2.98–2.78(m,1H),2.65(s,3H),1.17(d,J=6.8Hz,6H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氯-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3, 2-d]嘧啶-8-羧酰胺(41)
依据通用合成流程8的方法,使4-羟基-吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙胺二盐酸盐反应,制备标题化合物41,为乳白色固体。LC/MS[451(M+H)];1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.20(s,1H),9.01(d,1H),8.56(d,1H),8.39(dd,1H),8.20(d,1H),8.05(s,1H),7.80(d,1H),7.68(d,1H),5.38(t,1H),3.11(ddd,5H),2.84(dd,1H),1.93(p,2H)。IC50p70S6K:1.6nM,Akt:11nM
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,4-d]嘧 啶-8-羧酸酰胺(42)
依据通用合成流程8的方法,使4-羟基-吡啶并[3,2-d]嘧啶-8-羧酰胺(G)和4-羟基-吡啶并[3,4-d]嘧啶-8-羧酰胺(H)的混合物与N-[(S)-2-氨基-2-(4-氯-3-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备化合物42。LC/MS[425(M+H)];1HNMR(500MHz,DMSO-d6)δ9.92(s,1H),9.28(s,1H),9.00(d,J=4.5Hz,1H),8.55(s,1H),8.38(d,J=4.5Hz,1H),8.17(s,1H),8.00(s,1H),7.77(d,J=7.4Hz,1H),7.67(d,J=8.4Hz,1H),5.64–5.44(m,1H),3.20–3.09(m,1H),3.04–2.88(m,1H),2.30(s,3H)。
4-[(S)-1-(3,4-二-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酰胺(43)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3,4-二-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物43,为白色固体。LC/MS[459(M+H)];1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.34(s,1H),9.02(d,1H),8.54(s,1H),8.39(d,1H),8.18(d,2H),7.98(q,2H),5.62(s,1H),3.16(dd,1H),3.00(dd,1H),2.32(d,3H)。
4-[(S)-1-(4-氯-3-甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(44)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氯-3-甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物44,为白色固体。LC/MS[371(M+H)];1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),9.08(s,1H),8.99(d,J=4.3Hz,1H),8.53(s,1H),8.37(d,J=4.3Hz,1H),8.17(s,1H),7.43(s,1H),7.34(d,J=8.2Hz,1H),7.29(d,J=8.1Hz,1H),5.54–5.26(m,1H),3.21–3.03(m,1H),3.00–2.77(m,1H),2.30(s,6H),1.78(s,1H)。
4-[(S)-1-(4-氯-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰 胺(45)
依据通用合成流程8的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氯-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物45,为白色固体。LC/MS[357(M+H)]。
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氯-3-甲基-苯基)-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(46)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(4-氯-3-甲基-苯基)-乙胺二盐酸盐反应,制备标题化合物46,为乳白色固体。LC/MS[397(M+H)];1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),9.01(s,1H),8.99(d,J=4.5Hz,1H),8.53(s,1H),8.37(d,J=4.5Hz,1H),8.17(s,1H),7.45(s,1H),7.39–7.24(m,2H),5.34–5.17(m,1H),3.20–2.98(m,5H),2.83–2.71(m,1H),2.29(s,3H),2.01–1.84(m,1H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(3-氯-4-氰基-苯基)-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(47)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与4-((S)-1-氨基-2-氮杂环丁烷-1-基-乙基)-2-氯-苯甲腈盐酸盐反应,制备标题化合物47,为白色固体。LC/MS[409(M+H)];1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.16(d,1H),9.03(d,1H),8.56(s,1H),8.40(d,1H),8.18(s,1H),7.93(d,1H),7.66(d,1H),5.35(s,1H),3.27–2.97(m,2H),2.88(d,2H),2.01–1.83(m,4H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(3-二氟甲基-4-氟-苯基)-乙基氨基]-吡啶并[3, 2-d]嘧啶-8-羧酸酰胺(48)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(3-二氟甲基-4-氟-苯基)-乙胺盐酸盐反应,制备标题化合物48,为白色固体。LC/MS[409(M+H)];1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.09(d,1H),9.02(d,1H),8.55(s,1H),8.39(d,1H),8.18(s,1H),7.58(t,1H),7.52(d,1H),7.45(d,1H),7.29(s,1H),7.16(s,1H),7.02(s,1H),5.34(dd,1H),3.20–3.02(m,4H),2.84(dd,2H),1.99–1.85(m,2H)。
4-[(S)-1-(4-氟-3-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(49)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氟-3-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物49,为白色固体。LC/MS[409(M+H)];1H NMR(400MHz,乙腈-d3)δ10.30(s,1H),8.94(d,1H),8.47(d,3H),7.72(dd,2H),7.28(t,1H),6.59(s,1H),5.41(d,1H),3.13(dd,1H),3.03(dd,1H),2.38(s,3H)。
4-[(S)-2-二甲基氨基-1-(4-氟-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(50)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-1-(4-氟-3-三氟甲基-苯基)-N2,N2-二甲基-乙烷-1,2-二胺盐酸盐反应,制备标题化合物50,为白色固体。LC/MS[423(M+H)];1H NMR(400MHz,乙腈-d3)δ10.31(s,1H),8.96(d,1H),8.55–8.42(m,3H),7.90–7.73(m,2H),7.33(t,1H),6.63(s,1H),5.55(s,1H),3.20(s,1H),2.81(s,1H),2.17(s,6H)。
4-[(S)-1-(3-二氟甲基-4-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(51)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-二氟甲基-4-氟-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物51,为白色固体。LC/MS[391(M+H)]。
4-[(S)-1-(4-氟-3-三氟甲基-苯基)-2-异丙基氨基-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(52)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氟-3-三氟甲基-苯基)-乙基]-N-异丙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物52,为白色固体。LC/MS[437(M+H)];1H NMR(400MHz,乙腈-d3)δ10.31(s,1H),8.93(d,1H),8.49(t,3H),7.79–7.64(m,2H),7.28(t,1H),6.59(s,1H),5.38(s,1H),3.14(dt,2H),2.89–2.72(m,1H),1.03(t,6H)。
4-[(S)-1-(4-氯-3-氟-苯基)-2-二甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(53)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-1-(4-氯-3-氟-苯基)-N2,N2-二甲基-乙烷-1,2-二胺盐酸盐反应,制备标题化合物53,为白色固体。LC/MS[390(M+H)];1H NMR(400MHz,乙腈-d3)δ10.34(s,1H),8.96(d,1H),8.49(d,2H),8.35(s,1H),7.46(t,1H),7.35(d,1H),7.28(d,1H),6.62(s,1H),5.26(d,1H),2.93(t,1H),2.60(dd,1H),2.29(s,6H)。
4-[(S)-1-(4-氯-3-氟-苯基)-2-异丙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(54)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氯-3-氟-苯基)-乙基]-N-异丙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物54,为白色固体。LC/MS[404(M+H)]。
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-异丙基氨基-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(55)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氯-3-三氟甲基-苯基)-乙基]-N-异丙基-4-硝基-苯磺酰胺反应,制备标题化合物55,为白色固体。LC/MS[454(M+H)];1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.26(s,1H),9.01(d,1H),8.55(s,1H),8.38(d,1H),8.17(s,1H),8.01(s,1H),7.76(d,1H),7.67(d,1H),5.47(s,1H),3.15(d,1H),3.02(s,1H),2.80–2.69(m,1H),0.96(dd,6H)。
4-[(S)-2-乙基氨基-1-(4-氟-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(56)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氟-3-三氟甲基-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物56,为白色固体。LC/MS[423(M+H)];1H NMR(400MHz,DMSO-d6)δ9.93(d,1H),9.26(s,1H),9.00(d,1H),8.54(s,1H),8.37(d,1H),8.16(d,1H),7.92(dd,1H),7.82(ddd,1H),7.44(dd,1H),5.51(m,1H),3.17(dd,1H),2.99(dd,1H),2.62–2.52(q,2H),0.97(t,3H)。
4-[(S)-1-(3-氯-4-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧 酸酰胺(57)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氯-4-氟-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物57,为白色固体。LC/MS[376(M+H)];1H NMR(400MHz,乙腈-d3)δ10.31(s,1H),8.93(d,1H),8.46(dd,3H),7.51(d,1H),7.36(s,1H),7.20(t,1H),6.58(s,1H),5.34(dd,1H),3.11(dd,1H),3.00(dd,1H),2.37(s,3H)。
4-[(S)-2-乙基氨基-1-(2,4,5-三氟-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(58)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(2,4,5-三氟-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物58,为白色固体。LC/MS[391(M+H)];1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.13(s,1H),9.02(d,1H),8.57(s,1H),8.38(t,1H),8.18(s,1H),7.66(dd,1H),7.53(td,1H),5.71(s,1H),3.15(dd,1H),2.95(dd,1H),2.67–2.55(q,2H),0.98(t,3H)。
4-[(S)-1-(3,4-二-三氟甲基-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(59)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3,4-二-三氟甲基-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物59,为白色固体。LC/MS[473(M+H)];1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.35(s,1H),9.03(d,1H),8.55(s,1H),8.40(d,1H),8.19(d,2H),7.99(q,2H),5.60(s,1H),3.25–3.15(m,1H),3.06(s,1H),2.58(d,2H),0.98(t,3H)。
4-[(S)-2-甲基氨基-1-(2,4,5-三氟-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(60)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(2,4,5-三氟-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物60,为白色固体。LC/MS[377(M+H)]。
4-[(S)-1-(3-氯-4-氟-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧 酸酰胺(61)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氯-4-氟-苯基)-乙基]-N-乙基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物61,为白色固体。LC/MS[390(M+H)];1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.16(s,1H),9.00(d,1H),8.56(s,1H),8.38(d,1H),8.17(s,1H),7.71(dd,1H),7.52–7.43(m,1H),7.35(t,1H),5.44(s,1H),3.16(dd,1H),2.96(dd,1H),2.57(dt,2H),0.98(t,3H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氟-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3, 2-d]嘧啶-8-羧酸酰胺(62)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(4-氟-3-三氟甲基-苯基)-乙胺反应,制备标题化合物62,为白色固体。LC/MS[390(M+H)]。
4-[(S)-2-氮杂环丁烷-1-基-1-(3,4-二-三氟甲基-苯基)-乙基氨基]-吡啶并[3, 2-d]嘧啶-8-羧酸酰胺(63)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(3,4-二-三氟甲基-苯基)-乙胺反应,制备标题化合物63,为白色固体。LC/MS[485(M+H)]。
4-[(S)-1-(3-氯-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰 胺(64)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氯-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物64。LC/MS[357(M+H)]1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.20(br s,1H),9.00(d,1H),8.55(s,1H),8.39(d,1H),8.20(s,1H),7.56(m,1H),7.47–7.26(m,3H),5.48(s,1H),3.16(dd,1H),2.92(dd,1H),2.31(s,3H)。
4-[(S)-1-(3-溴-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰 胺(65)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-溴-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物65。LC/MS[401,403(M+H)]1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.19(s,1H),9.01(d,1H),8.55(s,1H),8.39(d,1H),8.19(s,1H),7.70(m,1H),7.52–7.38(m,3H),7.29(m,1H),5.48(s,1H),3.15(dd,1H),2.91(dd,1H),2.31(s,3H)。
4-[(S)-1-(3-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰 胺(66)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氟-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物66。LC/MS[341(M+H)]。
4-[(S)-1-(4-氟-3-甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(67)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-氟-3-甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备标题化合物67。LC/MS[355(M+H)]1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.07(s,1H),8.99(d,1H),8.54(s,1H),8.38(d,1H),8.17(s,1H),7.38(m,1H),7.30(m,1H),7.07(m,1H),5.45(s,1H),3.15(dd,1H),2.89(dd,1H),2.32(s,3H),2.21(s,3H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8- 羧酸酰胺(68)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙胺盐酸盐反应,制备标题化合物68。LC/MS[367(M+H)]1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.07(d,1H),9.01(d,1H),8.56(s,1H),8.39(d,1H),8.17(s,1H),7.34(m,3H),7.07(m,1H),5.36(m,1H),3.13(m,4H),2.86(m,1H),1.96(m,2H)。
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-(3-氟-氮杂环丁烷-1-基)-乙基氨基]-吡 啶并[3,2-d]嘧啶-8-羧酸酰胺(69)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-1-(4-氯-3-三氟甲基-苯基)-2-(3-氟-氮杂环丁烷-1-基)-乙胺盐酸盐反应,制备标题化合物69。LC/MS[469(M+H)]1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),9.26(d,1H),9.01(d,1H),8.57(s,1H),8.39(d,1H),8.17(s,1H),8.08(s,1H),7.82(m,1H),7.68(m,1H),5.45(m,1H),5.12(m,1H),3.59(m,2H),3.21(m,2H),2.95(m,5.6Hz,1H)。
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-(3-羟基-氮杂环丁烷-1-基)-乙基氨基]- 吡啶并[3,2-d]嘧啶-8-羧酸酰胺(70)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-1-(4-氯-3-三氟甲基-苯基)-2-(3-羟基-氮杂环丁烷-1-基)-乙胺盐酸盐反应,制备标题化合物70。LC/MS[467(M+H)]。
4-[(R)-2-氮杂环丁烷-1-基-1-(4-氯-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3, 2-d]嘧啶-8-羧酰胺(71)
依据通用合成流程7的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(R)-2-氮杂环丁烷-1-基-1-(4-氯-3-三氟甲基-苯基)-乙胺盐酸盐反应,制备标题化合物71。LC/MS[451(M+H)]。
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧 啶-8-羧酸酰胺(72)
依据通用合成流程10的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酸甲酯(I)与N-[(S)-2-氨基-2-(4-氯-3-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺反应,制备标题化合物72。LC/MS[425(M+H)];1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.29(s,1H),9.00(d,J=4.6Hz,1H),8.54(s,1H),8.38(d,J=4.5Hz,1H),8.19(s,1H),8.00(s,1H),7.77(d,J=8.4Hz,1H),7.66(d,J=8.3Hz,1H),5.53(s,1H),3.13(dd,J=12.3,8.3Hz,1H),2.94(dd,J=12.4,5.8Hz,1H),2.29(s,3H),1.92(s,1H)。
4-[(S)-2-氮杂环丁烷-1-基-1-(3-氯4-三氟甲氧基-苯基)-乙基氨基]-吡啶并 [3,2-d]嘧啶-8-羧酰胺(73)
依据通用合成流程11的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与(S)-2-氮杂环丁烷-1-基-1-(-(3-氯4-三氟甲氧基-苯基)-乙胺盐酸盐反应,制备33mg标题化合物73,为白色固体。LC/MS[467(M+H)];1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.12(d,J=8.1Hz,1H),9.00(d,J=4.5Hz,1H),8.56(s,1H),8.38(d,J=4.5Hz,1H),8.17(s,1H),7.85(s,1H),7.58(d,J=8.1Hz,1H),7.51(d,J=8.6Hz,1H),5.33(q,J=7.7Hz,1H),3.13(hept,J=6.7Hz,4H),3.09–2.99(m,1H),2.82(dd,J=12.0,5.8Hz,1H),1.92(p,J=7.0Hz,2H)。
4-[(S)-1-(3-氯-4-三氟甲氧基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酰胺(74)
依据通用合成流程11的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3-氯4-三氟甲氧基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺盐酸盐反应,制备57mg标题化合物74,为白色固体。LC/MS[441(M+H)])];1H NMR(400MHz,DMSO-d6)δ9.92(d,J=3.5Hz,1H),9.35–9.22(m,1H),9.01(d,J=4.4Hz,1H),8.57(s,1H),8.39(d,J=4.5Hz,1H),8.18(d,J=3.9Hz,1H),7.83(d,J=1.9Hz,1H),7.61–7.47(m,2H),5.60(s,1H),3.26(d,J=11.3Hz,1H),3.05(d,J=12.4Hz,1H),2.37(s,3H)。
4-[(S)-1-(3,4-二氯-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧 酰胺(75)
依据通用合成流程11的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(3,4-二氯-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺反应,制备标题化合物75。LC/MS[391(M+H)],1H NMR(400MHz,DMSO-d6)δ9.94(d,1H),9.17(d,1H),9.00(d,1H),8.55(s,1H),8.38(d,1H),8.17(d,1H),7.76(d,1H),7.58(d,1H),7.45(dd,1H),5.46(s,1H),3.13(dd,1H),2.92(dd,1H),2.30(s,3H)。
4-[(S)-2-甲基氨基-1-(4-甲基-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d] 嘧啶-8-羧酸酰胺(76)
依据通用合成流程11的方法,使4-羟基吡啶并[3,2-d]嘧啶-8-羧酰胺(G)与N-[(S)-2-氨基-2-(4-甲基-3-三氟甲基-苯基)-乙基]-N-甲基-4-硝基-苯磺酰胺反应,制备化合物76。LC-MS[405(M+1)];1H NMR(400MHz,DMSO-d6)d 9.95(d,J=3.4Hz,1H),9.21(d,J=8.5Hz,1H),9.00(d,J=4.6Hz,1H),8.54(s,1H),8.38(d,J=4.5Hz,1H),8.16(d,J=3.5Hz,1H),7.80(s,1H),7.63(d,J=7.9Hz,1H),7.38(d,J=8.1Hz,1H),5.51(s,1H),3.15(dd,J=12.4,8.4Hz,1H),2.92(dd,J=12.3,5.5Hz,1H),2.40(s,4H),2.30(s,3H)。
实施例3:P70S6K酶试验
将P70S6K抑制剂化合物稀释,并铺于96孔板中。将包含以下组分的反应混合液加入该化合物板中以开始酶反应:将P70S6K(3nM,T412E突变体,Millipore)与24μM ATP在试验缓冲液中混合,所述缓冲液包含100mM Hepes(pH 7.5)、5mM MgCl2、1mM DTT、0.015%Brij和1μM底物肽FITC-AHA-AKRRRLSSLRA-OH(源自S6核糖体蛋白质序列,FITC=异硫氰酸荧光素,AHA=6-氨基己酸)。将该反应物在25℃孵育90分钟,之后加入10mM EDTA以停止该反应。在Caliper Life Sciences Lab Chip3000分析底物和产物(磷酸化的)肽的比例,压力为-1.4psi,下游电压和下游电压分别为-3000和-700。在获得色谱图上,解析出产物峰在底物峰之前。为了评价化合物的抑制性能,按照如上所述测定了IC50值。
实施例4:AKT/PKB激酶试验
为了在Caliper Life Sciences Lab Chip 3000测定AKT的抑制作用,采用TTPMosquito液体处理仪器,在384孔板的每个孔内放置125nl在100%DMSO中适当浓度的抑制剂(用于绘制剂量反应曲线)。向该反应加入以下各组分至终浓度为12.5μl:
0.1ng/μl His-AKT(全长),(Invitrogen,Part#P2999,Lot#641228C);
160uM ATP(Fluka,02055);
1mM DTT(Sigma,D0632);
1mM MgCl2(Sigma,M1028);
1μM底物肽(序列FITC-AHA-GRPRTSSFAEG-NH2),由Tufts Peptide Synthesisservice合成;
100mM HEPES pH 7.5(Calbiochem,391338);以及
0.015%Brij-35(Sigma,B4184)。
反应在25℃培育90分钟,然后加入70μl终止缓冲液(100mM HEPES pH 7.5,0.015%Brij-35,10mM EDTA(Sigma,E7889))终止反应。
用Caliper LC 3000读取孔板,读取格式为芯片外迁移率试验格式(Off-Chipmobility shift assay format),采用具有12个吸入针的芯片,参数如下:筛选压力–2.3psi,上游电压–500,下游电压–3000。这些条件使得未磷酸化底物和磷酸化产物以不同峰分辨出来,因此可以直接测量底物转化为产物的百分比。将转化百分比与抑制剂浓度绘制成曲线,得到S形剂量应答曲线,基于该S形曲线可以计算IC50值。
表1列出了实施例部分中选定的化合物在P70S6K和AKT酶抑制试验中获得的值。
表中的数据的含义如下:
+++++:<25nM;
++++:25-100nM;
+++:101nM–500nM;
++:501nM–1000nM;
+:>1M。
表1:通式(I)所示的化合物对p70S6K和AKT酶的抑制
实施例5:药物制剂
(A)注射液瓶:将100g本发明化合物作为活性成分与5g磷酸二氢钠在3L再蒸馏水中的溶液用2N盐酸调它的pH至6.5,无菌过滤,转移到注射瓶中,无菌条件下冻干,并在无菌条件下密封。每个注射液瓶含有5mg活性成分。
(B)栓剂:将20g本发明化合物作为活性成分与100g大豆卵磷脂和1400g可可油混合,倒入模中,冷却。每片栓剂含20mg活性成分。
(C)溶液制剂:由1g作为活性成分的本发明化合物、9.38g NaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵在940mL再蒸馏水中制成一种溶液。将该溶液的pH调至6.8,再将该溶液配至1L,放射灭菌。该溶液以眼药水形式使用。
(D)软膏:在无菌条件下将500mg本发明化合物作为活性成分与99.5g凡士林混合。
(E)片剂:将1kg本发明化合物作为活性成分、4kg乳糖、1.2kg马铃薯粉、0.2kg滑石和0.1kg硬脂酸镁按照常规方法压成片剂,以致于每片含10mg活性成分。
(F)包衣片剂:类似实施例E压成片剂,然后按照常规方法用蔗糖包衣、马铃薯粉、滑石、黄芪胶和染料来包衣片剂。
(G)胶囊剂:将2kg本发明化合物作为活性成分按照常规方法导入硬胶囊中,以致于每个胶囊含20mg活性成分。
(H)安瓿剂:将1kg本发明化合物作为活性成分在60L再蒸馏水中的溶液无菌过滤,转移到安瓿中,无菌条件下冻干,并在无菌条件下密封。每个安瓿含有10mg活性成分。
(I)吸入喷雾剂:将14g本发明化合物作为活性成分溶解在10L等渗氯化钠溶液中,将该溶液转移至商业可买到的带泵机构的喷雾容器中。可将溶液喷入嘴或鼻内。一次喷射(约0.1ml)相当于一剂约0.14mg。
Claims (9)
1.一种化合物,其中所述化合物选自下列化合物:
4-(3-三氟甲基-苄基氨基)-苯并[d][1,2,3]三嗪-8-羧酰胺 (1);
4-((3,4-二氯苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (2);
4-((4-氯-3-(三氟甲基)苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (4);
4-(苄基氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (6);
4-((4-(三氟甲基)苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (8);
4-((3-氟苄基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (9);
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-甲氧基苯基)乙基)氨基)-苯并[d][1,2,3]三嗪-8-羧酰胺 (10);
(S)-4-((1-(4-氯-3-甲氧基苯基)-2-(二甲基氨基)乙基)氨基)-苯并[d][1,2,3]三嗪-8-羧酰胺 (11);
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氟-3-(三氟甲基)苯基)乙基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (12);
(S)-4-((1-(4-氯-3-(三氟甲基)苯基)-2-(二甲基氨基)乙基)氨基)苯并-[d][1,2,3]三嗪-8-羧酰胺 (13);
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-(三氟甲基)苯基)乙基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (14);
(S)-4-((1-(3,4-二氯苯基)-2-(二甲基氨基)乙基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (15);
(S)-4-((2-(氮杂环丁烷-1-基)-1-(3,4-二氯苯基)乙基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (16);
(S)-4-((1-(4-氯-3-氰基苯基)-2-(二甲基氨基)乙基)氨基)-苯并[d][1,2,3]三嗪-8-羧酰胺 (17);
(S)-4-((2-(氮杂环丁烷-1-基)-1-(4-氯-3-氰基苯基)乙基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (18);
4-((4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (21);
4-((4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)苯并[d][1,2,3]三嗪-8-羧酰胺 (22);
4-[4-(3-氯-4-氟-苯基)-哌啶-3-基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺 (23);
4-((4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)吡啶并[3,2-d]嘧啶-8-羧酰胺 (25);
4-[(S)-1-(3-氟-4-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (26);
4-[(S)-2-氮杂环丁烷-1-基-1-(4-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (27);
4-[(S)-1-(3-溴-4-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (28);
4-[(S)-2-乙基氨基-1-(3-氟-4-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (29);
4-[(S)-1-(3-溴-4-氟-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (30);
4-[(S)-1-(2,5-二氟-4-甲氧基-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (31);
4-[(S)-1-(2,5-二氟-4-甲氧基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (32);
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (33);
4-[(S)-2-乙基氨基-1-(3-氟-5-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (34);
4-[(S)-1-(3-氟-5-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (35);
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氯-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (36);
4-[(S)-2-氮杂环丁烷-1-基-1-(4-异丙基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (37);
4-[(S)-2-甲基氨基-1-(4-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (38);
4-[(S)-1-(4-异丙基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (39);
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氯-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺 (41);
4-[(S)-1-(3,4-二-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺 (43);
4-[(S)-1-(4-氯-3-甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (44);
4-[(S)-1-(4-氯-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺(45);
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氯-3-甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (46);
4-[(S)-2-氮杂环丁烷-1-基-1-(3-氯-4-氰基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (47);
4-[(S)-2-氮杂环丁烷-1-基-1-(3-二氟甲基-4-氟-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (48);
4-[(S)-1-(4-氟-3-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (49);
4-[(S)-2-二甲基氨基-1-(4-氟-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (50);
4-[(S)-1-(3-二氟甲基-4-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (51);
4-[(S)-1-(4-氟-3-三氟甲基-苯基)-2-异丙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (52);
4-[(S)-1-(4-氯-3-氟-苯基)-2-二甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (53);
4-[(S)-1-(4-氯-3-氟-苯基)-2-异丙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (54);
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-异丙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (55);
4-[(S)-2-乙基氨基-1-(4-氟-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (56);
4-[(S)-1-(3-氯-4-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (57);
4-[(S)-2-乙基氨基-1-(2,4,5-三氟-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (58);
4-[(S)-1-(3,4-二-三氟甲基-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (59);
4-[(S)-2-甲基氨基-1-(2,4,5-三氟-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (60);
4-[(S)-1-(3-氯-4-氟-苯基)-2-乙基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (61);
4-[(S)-2-氮杂环丁烷-1-基-1-(4-氟-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (62);
4-[(S)-2-氮杂环丁烷-1-基-1-(3,4-二-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (63);
4-[(S)-1-(3-氯-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺(64);
4-[(S)-1-(3-溴-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺(65);
4-[(S)-1-(3-氟-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺(66);
4-[(S)-1-(4-氟-3-甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (67);
4-[(S)-2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (68);
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-(3-氟-氮杂环丁烷-1-基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (69);
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-(3-羟基-氮杂环丁烷-1-基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (70);
4-[(R)-2-氮杂环丁烷-1-基-1-(4-氯-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺 (71);
4-[(S)-1-(4-氯-3-三氟甲基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (72);
4-[(S)-2-氮杂环丁烷-1-基-1-(3-氯4-三氟甲氧基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺 (73);
4-[(S)-1-(3-氯-4-三氟甲氧基-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺 (74);
4-[(S)-1-(3,4-二氯-苯基)-2-甲基氨基-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酰胺(75);和
4-[(S)-2-甲基氨基-1-(4-甲基-3-三氟甲基-苯基)-乙基氨基]-吡啶并[3,2-d]嘧啶-8-羧酸酰胺 (76)。
2.一种药物,所述药物包含如权利要求1所述的至少一种化合物和/或其生理学上可接受的盐。
3.一种药物组合物,所述药物组合物包含作为活性成分的如权利要求1所述的至少一种化合物和/或其生理学上可接受的盐以及药学上耐受的赋形剂,任选地所述药物组合物还包含一或多种其它活性成分。
4.如权利要求1所述的化合物和/或其生理学上可接受的盐在制备用于预防性或治疗性治疗和/或监测由p70S6K或AKT活性引起、介导和/或蔓延的疾病的药物中的用途。
5.如权利要求4所述的用途,其中所述疾病选自以下组内:过度增殖性疾病、转移、炎症、视网膜病变、糖尿病、疼痛和再狭窄。
6.如权利要求4所述的用途,其中所述疾病选自以下组内:肿瘤、血管生成病症、和良性增生。
7.如权利要求4所述的用途,其中所述疾病选自以下组内:癌症、血管发生或血管生成相关性前列腺疾病、和胰腺炎。
8.如权利要求4所述的用途,其中所述疾病选自以下组内:肿瘤血管生成、血管瘤、神经胶质瘤、黑素瘤、卡波氏肉瘤、早产儿视网膜病变、糖尿病性视网膜病、牛皮癣、湿疹、硬皮病和年龄相关性黄斑变性。
9.如权利要求1所述的化合物和/或其生理学上可接受的盐在制备抑制p70S6激酶和AKT在系统中表达p70S6K和AKT的药物的用途。
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US201261731075P | 2012-11-29 | 2012-11-29 | |
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PCT/US2013/072141 WO2014085528A1 (en) | 2012-11-29 | 2013-11-27 | Azaquinazoline carboxamide derivatives |
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ES2967344T3 (es) | 2015-10-02 | 2024-04-29 | Sentinel Oncology Ltd | Derivados de 2-aminoquinazolina como inhibidores de cinasa p70s6 |
TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Hdac抑制劑與pd-l1抑制劑之組合治療 |
TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
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BR9713552A (pt) | 1996-11-27 | 2000-01-25 | Pfizer | Derivados de pirimidina bicìclicos condensados |
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